Nesprins (nuclear envelope spectrin repeat proteins) are a family of multi-isomeric scaffolding proteins. Nesprins form the LInker of Nucleoskeleton-and-Cytoskeleton (LINC) complex with SUN (Sad1p/UNC84) domain-containing proteins at the nuclear envelope, in association with lamin A/C and emerin, linking the nucleoskeleton to the cytoskeleton. The LINC complex serves as both a physical linker between the nuclear lamina and the cytoskeleton and a mechanosensor. The LINC complex has a broad range of functions and is involved in maintaining nuclear architecture, nuclear positioning and migration, and also modulating gene expression. Over 80 disease-related variants have been identified in SYNE-1/2 (nesprin-1/2) genes, which result in muscular or central nervous system disorders including autosomal dominant Emery–Dreifuss muscular dystrophy, dilated cardiomyopathy and autosomal recessive cerebellar ataxia type 1. To date, 17 different nesprin mouse lines have been established to mimic these nesprin-related human diseases, which have provided valuable insights into the roles of nesprin and its scaffold LINC complex in a tissue-specific manner. In this review, we summarise the existing nesprin mouse models, compare their phenotypes and discuss the potential mechanisms underlying nesprin-associated diseases.

Introduction

Nesprins (nuclear envelope spectrin repeat proteins) are the latest identified members of the spectrin repeat (SR)-containing protein family [1]. To date, six genes encoding for different KASH domain-containing proteins named as nesprins-1, -2, -3, -4, lymphoid-restricted membrane protein (LRMP) and KASH5 have been identified in mammals [16].

Nesprin-1 and -2 are encoded by synaptic nuclear envelope (SYNE)-1 and -2 genes. The longest isoforms of nesprin-1 and -2 are the second (∼1MDa) and third (∼800 kDa) largest proteins in man [1]. The general structure of these proteins comprises an evolutionarily conserved Klarsicht/ANC-1/Syne Homology (KASH) domain at the C-terminus that targets nesprin family members to the nuclear envelope (NE); a central rod domain containing multiple SRs that mediate protein–protein interactions; and paired Calponin Homology (CH) domains at the N-terminus, also known as the actin-binding domain (ABD) that binds to filamentous actin (F-actin) [1,2]. Nesprin-1/2 have diverse isoforms, which vary in length and differ in domain composition due to extensive alternative transcription initiation, termination and splicing [7] (for an extensive review of nesprin-1/2 isoforms, we refer readers to [8]). Giant nesprin-1/2 isoforms are ubiquitously expressed, in particular nesprin-1 giant is enriched in vascular smooth muscle, while smaller nesprin-1/2 isoforms, such as nesprin-1α2, 2α1 and 2εƐ2, are specifically expressed in skeletal and cardiac muscle [1,9,10]. Nesprin-1/2 localise at either side of the NE through their KASH domains. Smaller nesprin-1/2 isoforms interact with lamin A/C, emerin and the nucleoplasmic domain of Sad1p/UNC84 (SUN) domain-containing proteins SUN1/2 via their C-terminal SRs at the inner nuclear membrane (INM) [2,1113]; however, it remains unclear how INM localisation is established. Nesprin-1/2 giant isoforms localise at the outer nuclear membrane (ONM) and form the LInker of Nucleoskeleton-and-Cytoskeleton (LINC) complex via associations between their KASH domains and the SUN domains of SUN1/2 in the perinuclear space (PNS) [14,15]. The LINC complex tethers the NE to cytoskeletal elements including actin filaments and the microtubule (MT) network [1619]. This molecular linking network is pivotal in regulating nuclear integrity, maintaining nuclear-cytoskeleton coupling, and participating in mechanotransduction, nuclear migration and positioning especially in muscle cell differentiation [2,8,17,18,20,21].

Nesprin-3, -4, LRMP and KASH5 are encoded by the SYNE-3, -4, LRMP and KASH5 genes respectively and are much smaller than giant nesprin-1/2. They contain the KASH domain at the C-terminus and lack the N-terminal CH domains [3,4,6]. Nesprin-3 links the nucleus to intermediate filaments (IFs) via an interaction with plectin and regulates cell morphology, perinuclear cytoskeletal architecture and cell polarisation [3,22,23]. Differing from the ubiquitously expressed nesprin-1/2/3, nesprin-4 is predominately expressed in epithelial cells; KASH5 is limited to meiotic cells, while LRMP is rich in zebrafish zygotes and also expressed in the taste bud cells of the tongue in mammals [4,6,24,25]. Nesprin-4, KASH5 and LRMP are involved in the MT-associated LINC complex formation and function. Nesprin-4 recruits kinesin-1 to the NE and is involved in MT-dependent nuclear positioning [4]. KASH5 participates in MT-driven telomere movement and chromosome pairing during mammalian meiosis, whereas LRMP mediates centrosome–nucleus attachment by associating with the MT-dynein/dynactin complex, although this has only been shown in zebrafish zygotes to date [24,26].

The ability of nesprin family members to link the nucleus with different cytoskeletal elements has led to the assumption that they primarily function as nucleoskeleton and cytoskeleton linkers. Intriguingly, many nesprin-1/2 isoforms that lack KASH domains exist and localise to various subcellular compartments, such as the sarcomere, sarcoplasmic reticulum, mitochondria, focal adhesions, Golgi and promyelocytic leukaemia (PML) bodies, suggesting that nesprins possess additional functions [2,7,27,28]. So far, over 80 disease-associated variants have been identified in SYNE-1/2 genes, which result in muscular or central nervous system (CNS) disorders including autosomal dominant Emery–Dreifuss muscular dystrophy (EDMD), dilated cardiomyopathy (DCM) and autosomal recessive cerebellar ataxia type 1 (ARCA1) [12,2937].

To elucidate the roles of nesprin mutations in pathogenesis of these diseases, 17 different nesprin mouse lines have been established and characterised, providing valuable insights into the roles of nesprins and the LINC complex in different tissues (Figure 1 and Table 1). In this review, we summarise all the existing nesprin mouse models into two categories: (1) nesprin-1/2 mouse models with skeletal and cardiac muscle phenotypes and (2) all other nesprin mouse models. We specifically focus on the cardiac and skeletal muscle defects in nesprin-1/2 mouse models and discuss the potential mechanisms underlying nesprin-associated diseases.

Nesprin-1/2 mouse models.

Figure 1.
Nesprin-1/2 mouse models.

Various nesprin-1/2 mouse models were generated via targeting to different regions of Syne-1 and Syne-2 genes. The colours indicate different research groups who generated the models (Red—Noegel group [17]; Blue—Han group [41,42]; Violet—McNally group [38]; Green—Chen group [40,49,50]; Grey—Hodzic group [57]). Nesprin-1/2 KASH DKO mice were generated via breeding nesprin-1 KASH KO with nesprin-2 KASH KO (Han group) [42]. Nesprin-1/2 C-terminal DKO mice were independently generated via crossing two established mouse lines: cardiac-specific nesprin-1 C-terminal KO and nesprin-2 C-terminal KO (Chen group) [40]. KO: knockout; DKO: double knockout; DN: dominant negative; csNesprin-1 C-terminal KO: cardiac-specific Nesprin-1 C-terminal KO.

Figure 1.
Nesprin-1/2 mouse models.

Various nesprin-1/2 mouse models were generated via targeting to different regions of Syne-1 and Syne-2 genes. The colours indicate different research groups who generated the models (Red—Noegel group [17]; Blue—Han group [41,42]; Violet—McNally group [38]; Green—Chen group [40,49,50]; Grey—Hodzic group [57]). Nesprin-1/2 KASH DKO mice were generated via breeding nesprin-1 KASH KO with nesprin-2 KASH KO (Han group) [42]. Nesprin-1/2 C-terminal DKO mice were independently generated via crossing two established mouse lines: cardiac-specific nesprin-1 C-terminal KO and nesprin-2 C-terminal KO (Chen group) [40]. KO: knockout; DKO: double knockout; DN: dominant negative; csNesprin-1 C-terminal KO: cardiac-specific Nesprin-1 C-terminal KO.

Table 1
Summarisation of nesprin mouse models
Gene Mice Targeted region Targeted tissue Strategy Affected organs Phenotypes and/or cellular changes Ref. 
Syne-1 Nesprin-1 KASH KO KASH domain Global Floxed deletion of the last exon of Syne-1 resulting in the deletion of last two exons (∼100 residues, including KASH domain) and inserted additional 61 amino acids without homology to any known proteins Heart
Skeletal muscle 
  • 49% new born litters died due to respiratory failure;

  • Rest of pups survived up to 1 year and developed heart conduction defect with left ventricle (LV) systolic dysfunction;

  • Smaller muscle fibres with mis-positioned nuclei;

  • Kyphoscoliosis.

 
[29,38
Nesprin-1 KASH DN Skeletal and cardiac Overexpression of the last 344 amino acid (SR74 to KASH domain) of Syne-1 under a muscle creatine kinase (MCK) promoter Skeletal muscle 
  • No overt phenotype reported;

  • In muscle fibre, synaptic nuclei failed to aggregate at the neuromuscular junction (NMJ).

 
[41
Nesprin-1 KASH KO  Global Targeted deletion of the last exon of Syne-1, including KASH domain Skeletal muscle 
  • No external phenotype reported;

  • In muscle fibre, synaptic nuclei completely lost at the NMJ, non-synaptic nuclei formed clusters or arrays.

 
[42
 
Nesprin-1 C-terminal KO C-terminus Global Floxed deletion of the 16th exon of Syne-1 resulting in a premature stop codon at the 13th exon (counted backward from the last exon), which ablated all nesprin-1 isoforms containing the C-terminal SRs region with or without KASH domain Skeletal muscle 
  • Over 60% mice died prenatally due to feeding insufficiency caused by muscle weakness;

  • In muscle fibres: mis-positioned nuclei and disrupted nuclei anchorage;

  • Reduced exercise capacity;

  • Normal heart function.

 
[49
Cardiac Nesprin-1 C-terminal KO Cardiac Crossing the Syne-1 KO mice [48] with Nkx2.5Cre to KO nesprin-1 C-terminus containing isoforms in heart Heart 
  • No overt cardiac functional defect;

  • Isolated cardiomyocytes showed changed nuclear morphology and perturbed mechanotransduction response.

 
[40
 
Nesprin-1 CH KO CH domain Global Floxed exon 9, encoding for the 2nd CH domain in Syne-1 and crossed with Sox2Cre mice to globally ablate expression of nesprin-1 CH domain containing isoforms None 
  • Survived up to 18 months;

  • No overt phenotypes reported.

 
[50
 
Nesprin-1α2 KO Isoform specific Global Floxed first exon which is unique to nesprin-1α2, then crossed with Sox2Cre mice to globally ablate expression of nesprin-1α2 Skeletal muscle 
  • 12% of litters survived;

  • In muscle fibres: nuclei were mis-positioned due to loss the interaction between nesprin-1α2 and microtubule motor protein kinesin-1.

 
[50
Syne-2 Nesprin-2 KASH DN KASH domain Skeletal and cardiac Overexpression of 183 amino acids of KASH containing domain of Syne-2 under the MCK promoter Skeletal muscle 
  • No external phenotype reported;

  • In muscle fibres, synaptic nuclei failed to aggregate at the NMJ.

 
[42
Nesprin-2 (GFP) KASH DN Reporter mouse to be induced by crossing with tissue specific Cre Overexpression of GFP fused to last 65 amino acids of KASH containing domain of Syne-2 using the Cre/Lox system, thus DN KASH2 can be expressed under a tissue specific promoter Retina
Brain
Skeletal muscle (due to tissue specific expression) 
  • In retina: nuclei mis-localised on the basal side of the outer nuclear layer

  • In Purkinje cells and skeletal muscle: exogenous EGFP-KASH2 was efficiently expressed, leading to mis-localised endogenous nesprin-1 and -2.

 
[5658
Nesprin-2 KASH KO  Global Targeted deletion of the last two exons of Syne-2 including KASH domain Retina
Brain 
  • In retina: thinner outer nuclear layer, electrophysiological dysfunction, mis-localisation of photoreceptor nuclei and defects in photoreceptor cell migration;

  • Defects in learning and memory due to the disrupted laminary structures.

 
[42,45,48
 
Nesprin-2 C-terminal KO C-terminus Global Floxed deletion of the 7th exon of Syne-2 (counted backward from the last exon), targeted to delete all nesprin-2 isoforms containing the C-terminal SRs region with or without KASH domain Heart 
  • Survived up to 18 months;

  • Isolated cardiomyocytes showed changed nuclear morphology and perturbed mechanotransduction response.

 
[40
 
Nesprin-2 CH KO CH domain Global Targeted deletion of the 2nd–4th exons of Syne-2 gene encoding the first CH domain Skin 
  • In skin: thicker epidermis, increased epithelial nuclear size and heavily misshaped nuclei

 
[17
Syne-1/2 Nesprin-1/2 C-terminal DKO C-terminus Global (nesprin-2 KO) & Cardiac (nesprin-1 KO) Crossing the cardiac specific nesprin-1 C-terminal KO mice with the global nesprin-2 C-terminal KO mice Heart 
  • Reduced LV wall thickness, LV systolic dysfunction, increased fibrosis and apoptosis;

  • Changed nuclear morphology, reduced density of heterochromatin, altered nuclear positioning and impaired mechanotransduction response.

 
[40
 
Nesprin-1/2 KASH DKO KASH domain Global Crossing the KASH1 KO mice (deletion of the last exon of Syne-1) with KASH2 KO mice (deletion of the last two exons of Syne-2Skeletal muscle
Brain 
  • New born litters failed to breath and died shortly after birth;

  • In muscle fibres: the synaptic-nuclei number were absent in the NMJ;

  • In brain: smaller brain with enlarged lateral ventricles, inverted layers, loss of other specific cell layers and disrupted laminary structure

 
[42,45
Syne-3/4 & KASH5 Nesprin-3 KO Nesprin-3 Global Targeted deletion of the 2nd exon of Syne-3, which contains the translation starting site for both nesprin-3α and nesprin-3β isoforms None 
  • No overt phenotype reported.

 
[59
 
Nesprin-4 KO Nesprin-4 Global Replacement of the 2nd to 6th exons with an IRES β-gal cassette, resulting in an effectively null allele Ear 
  • Impaired the localisation of nuclei from the basal to apex in outer hair cells, leading to progressed hearing loss.

 
[60
 
KASH5 KO KASH5 Global Targeted deletion of 5th–8th exons which resulted in a premature stop codon, leading to a complete absence of KASH5 Reproductive system 
  • Defects of homologous chromosome pairing during spermatogenesis, resulting in infertility.

 
[61
Gene Mice Targeted region Targeted tissue Strategy Affected organs Phenotypes and/or cellular changes Ref. 
Syne-1 Nesprin-1 KASH KO KASH domain Global Floxed deletion of the last exon of Syne-1 resulting in the deletion of last two exons (∼100 residues, including KASH domain) and inserted additional 61 amino acids without homology to any known proteins Heart
Skeletal muscle 
  • 49% new born litters died due to respiratory failure;

  • Rest of pups survived up to 1 year and developed heart conduction defect with left ventricle (LV) systolic dysfunction;

  • Smaller muscle fibres with mis-positioned nuclei;

  • Kyphoscoliosis.

 
[29,38
Nesprin-1 KASH DN Skeletal and cardiac Overexpression of the last 344 amino acid (SR74 to KASH domain) of Syne-1 under a muscle creatine kinase (MCK) promoter Skeletal muscle 
  • No overt phenotype reported;

  • In muscle fibre, synaptic nuclei failed to aggregate at the neuromuscular junction (NMJ).

 
[41
Nesprin-1 KASH KO  Global Targeted deletion of the last exon of Syne-1, including KASH domain Skeletal muscle 
  • No external phenotype reported;

  • In muscle fibre, synaptic nuclei completely lost at the NMJ, non-synaptic nuclei formed clusters or arrays.

 
[42
 
Nesprin-1 C-terminal KO C-terminus Global Floxed deletion of the 16th exon of Syne-1 resulting in a premature stop codon at the 13th exon (counted backward from the last exon), which ablated all nesprin-1 isoforms containing the C-terminal SRs region with or without KASH domain Skeletal muscle 
  • Over 60% mice died prenatally due to feeding insufficiency caused by muscle weakness;

  • In muscle fibres: mis-positioned nuclei and disrupted nuclei anchorage;

  • Reduced exercise capacity;

  • Normal heart function.

 
[49
Cardiac Nesprin-1 C-terminal KO Cardiac Crossing the Syne-1 KO mice [48] with Nkx2.5Cre to KO nesprin-1 C-terminus containing isoforms in heart Heart 
  • No overt cardiac functional defect;

  • Isolated cardiomyocytes showed changed nuclear morphology and perturbed mechanotransduction response.

 
[40
 
Nesprin-1 CH KO CH domain Global Floxed exon 9, encoding for the 2nd CH domain in Syne-1 and crossed with Sox2Cre mice to globally ablate expression of nesprin-1 CH domain containing isoforms None 
  • Survived up to 18 months;

  • No overt phenotypes reported.

 
[50
 
Nesprin-1α2 KO Isoform specific Global Floxed first exon which is unique to nesprin-1α2, then crossed with Sox2Cre mice to globally ablate expression of nesprin-1α2 Skeletal muscle 
  • 12% of litters survived;

  • In muscle fibres: nuclei were mis-positioned due to loss the interaction between nesprin-1α2 and microtubule motor protein kinesin-1.

 
[50
Syne-2 Nesprin-2 KASH DN KASH domain Skeletal and cardiac Overexpression of 183 amino acids of KASH containing domain of Syne-2 under the MCK promoter Skeletal muscle 
  • No external phenotype reported;

  • In muscle fibres, synaptic nuclei failed to aggregate at the NMJ.

 
[42
Nesprin-2 (GFP) KASH DN Reporter mouse to be induced by crossing with tissue specific Cre Overexpression of GFP fused to last 65 amino acids of KASH containing domain of Syne-2 using the Cre/Lox system, thus DN KASH2 can be expressed under a tissue specific promoter Retina
Brain
Skeletal muscle (due to tissue specific expression) 
  • In retina: nuclei mis-localised on the basal side of the outer nuclear layer

  • In Purkinje cells and skeletal muscle: exogenous EGFP-KASH2 was efficiently expressed, leading to mis-localised endogenous nesprin-1 and -2.

 
[5658
Nesprin-2 KASH KO  Global Targeted deletion of the last two exons of Syne-2 including KASH domain Retina
Brain 
  • In retina: thinner outer nuclear layer, electrophysiological dysfunction, mis-localisation of photoreceptor nuclei and defects in photoreceptor cell migration;

  • Defects in learning and memory due to the disrupted laminary structures.

 
[42,45,48
 
Nesprin-2 C-terminal KO C-terminus Global Floxed deletion of the 7th exon of Syne-2 (counted backward from the last exon), targeted to delete all nesprin-2 isoforms containing the C-terminal SRs region with or without KASH domain Heart 
  • Survived up to 18 months;

  • Isolated cardiomyocytes showed changed nuclear morphology and perturbed mechanotransduction response.

 
[40
 
Nesprin-2 CH KO CH domain Global Targeted deletion of the 2nd–4th exons of Syne-2 gene encoding the first CH domain Skin 
  • In skin: thicker epidermis, increased epithelial nuclear size and heavily misshaped nuclei

 
[17
Syne-1/2 Nesprin-1/2 C-terminal DKO C-terminus Global (nesprin-2 KO) & Cardiac (nesprin-1 KO) Crossing the cardiac specific nesprin-1 C-terminal KO mice with the global nesprin-2 C-terminal KO mice Heart 
  • Reduced LV wall thickness, LV systolic dysfunction, increased fibrosis and apoptosis;

  • Changed nuclear morphology, reduced density of heterochromatin, altered nuclear positioning and impaired mechanotransduction response.

 
[40
 
Nesprin-1/2 KASH DKO KASH domain Global Crossing the KASH1 KO mice (deletion of the last exon of Syne-1) with KASH2 KO mice (deletion of the last two exons of Syne-2Skeletal muscle
Brain 
  • New born litters failed to breath and died shortly after birth;

  • In muscle fibres: the synaptic-nuclei number were absent in the NMJ;

  • In brain: smaller brain with enlarged lateral ventricles, inverted layers, loss of other specific cell layers and disrupted laminary structure

 
[42,45
Syne-3/4 & KASH5 Nesprin-3 KO Nesprin-3 Global Targeted deletion of the 2nd exon of Syne-3, which contains the translation starting site for both nesprin-3α and nesprin-3β isoforms None 
  • No overt phenotype reported.

 
[59
 
Nesprin-4 KO Nesprin-4 Global Replacement of the 2nd to 6th exons with an IRES β-gal cassette, resulting in an effectively null allele Ear 
  • Impaired the localisation of nuclei from the basal to apex in outer hair cells, leading to progressed hearing loss.

 
[60
 
KASH5 KO KASH5 Global Targeted deletion of 5th–8th exons which resulted in a premature stop codon, leading to a complete absence of KASH5 Reproductive system 
  • Defects of homologous chromosome pairing during spermatogenesis, resulting in infertility.

 
[61

Abbreviations: KO: knockout; DKO: double knockout; DN: dominant negative.

Nesprin-1 KASH KO: the nesprin-1 KASH KO mouse model generated in Prof. McNally's Laboratory.

Nesprin-1 KASH KO: the nesprin-1 KASH KO mouse model generated in Prof. Han's Laboratory.

Nesprin-1/2 mouse models with muscle disorders

A nesprin mouse model with both skeletal and cardiac muscle disorders

Nesprin-1 KASH Knockout (KO)

The only nesprin mouse model that demonstrated both EDMD and DCM-like phenotypes was generated via global targeted deletion of the last exon of the Syne-1 gene leading to removal of the last two exons that included the KASH domain in Prof. McNally's Laboratory; we renamed this mouse model as Nesprin-1 KASH KO [29,38]. The KASH1 KO pups had a high perinatal mortality (49%) due to un-inflated lungs causing respiratory failure [38]. Surviving litters exhibited EDMD and DCM-like phenotypes, including hind-limb weakness, abnormal gaits, kyphoscoliosis, muscle pathology, conduction defects (CDs) and left ventricular (LV) systolic dysfunction [38]. The surface electrocardiogram (ECG) showed CDs presented earlier in atria than in ventricles and reduced LV fractional shortening, which was similar to observations described in patients with DCM and conduction system defects [29,39].

Cardiomyocytes (CMs) derived from KASH1 KO mice displayed elongated nuclear morphology, large invaginations of the NE and reduced levels of heterochromatin [29]. Reduced muscle fibre size accompanied with centralised nuclei was also evident in skeletal muscle biopsies, indicating defective nuclear positioning [38]. Interactions between nesprin-1 and SUN2 were disrupted, although lamin A/C, emerin and SUN2 remained staining at the NE [38]. The major limitation for this mouse model was that the additional 61 amino acid insertion replaced the KASH domain in KASH-containing nesprin-1 mutants. This fusion potentially created dominant negative (DN) nesprin-1 constructs that might contribute to the muscle phenotypes.

Nesprin-1/2 mouse model with cardiac muscle disorders

Nesprin-1/2 C-terminal double KO (DKO)

The nesprin-1/2 C-terminal DKO mouse model was independently generated in Prof. Chen's Laboratory, by crossing two previously established mouse lines: cardiac specific nesprin-1 C-terminal KO mice and global nesprin-2 C-terminal KO mice [40]. DKO hearts were theoretically ablated of all nesprin-1 and -2 isoforms containing the C-terminal SR region with or without the KASH domain. This included the muscle-specific isoforms nesprin-1α2, nesprin-2α1 and nesprin-2εƐ2. No overt cardiac and skeletal muscle dysfunction phenotypes were reported in either cardiac-specific nesprin-1 deletion or global nesprin-2 deletion mice previously [40]. However, DKO mice displayed early-onset cardiomyopathy: LV wall thickness and fractional shortening was decreased at 10 weeks and deteriorated over time [40]. Increased fibrosis and apoptosis were detected in DKO heart tissue and expression of foetal genes ANP, βMHC and profibrotic genes procollagen 1α1, 3α1 were also increased [40].

Similar to the nesprin-1 KASH KO mice, the CMs derived from this DKO mice also showed morphologically altered nuclei [40]. However, the LINC complex-associated components, lamin A/C and emerin, were mis-localised from the NE, although their expression levels remained unchanged in the DKO mice, indicating the compromised LINC complex was caused by defects in the localisation of these proteins rather than changes in expression levels [40]. Furthermore, when mechanical load was applied to DKO and WT CMs, there were dramatically up-regulated biomechanical responsive genes including egr-1, iex-1, c-jun, c-fos and c-myc in WT CMs, while expression of these genes was abrogated in DKO CMs [40]. These data demonstrate that nesprin-1/2 play essential roles in cardiac physiology, maintenance and responsiveness to biomechanical load.

Nesprin-1/2 mouse models with skeletal muscle disorders

Nesprin-1 KASH DN/KO, Nesprin-2 KASH DN/KO and Nesprin-1/2 KASH DKO

Five KASH1 and/or KASH2 domain mouse lines were generated in Professor Han's Laboratory to investigate nesprin functions in striated muscle [41,42]. A striated muscle-specific nesprin-1 KASH DN mouse line was generated by using a muscle creatine kinase (MCK) promoter that enabled highly preferential expression of nesprin-1 C-terminal 344 amino acids including the last SR and KASH domain in skeletal and cardiac muscle [41,43,44]. Utilising the same strategy, striated muscle-specific nesprin-2 KASH DN mice were also established [42]. Of note, although this strategy was designed to target skeletal and cardiac muscle, smooth muscle may also have been affected and contribute to this phenotype. However, this remains to be tested. In addition, global KASH1 KO and KASH2 KO mice were generated via targeted deletion of the last one (Syne-1) and two (Syne-2) exons, respectively, which encode for the KASH domains of the Syne-1 and Syne-2 genes [42]. The global nesprin-1/2 KASH DKO line was generated by crossing the KASH1 KO with KASH2 KO [42].

All KO/DN strains were viable, with the exception of the KASH1/2 DKO litters that died after birth due to respiratory failure, which was suggested to be probably secondary to the CNS development defect [42,45]. Defects in other organs/tissues that are rich in nesprin-1/2 isoforms could also potentially contribute to this lethality. For example: the function of smooth muscle (containing mainly nesprin-1 giant isoform) and/or diaphragm (skeletal muscle containing mainly nesprin-1α2 and nesprin-2α1) could be perturbed and lead to impaired dilation of the bronchi and abnormal volume/pressure changes of the thoracic cavity during respiration [9,46,47]. However, no overt cardiac or skeletal muscular-related symptoms were reported in the KASH1/2 DKO mice [41,42].

Nesprin-1 plays major roles in nuclear migration and myogenesis. Nuclear positioning defects in muscle fibres were also prevalent in skeletal muscle biopsies derived from these mice. The KASH1 KO and KASH1/2 DKO displayed the most severe nuclear positioning phenotypes with the total loss of synaptic nuclei and clustered non-synaptic nuclei [41,42]. The difference in severity between the strains is potentially explained because a low level of endogenous nesprin-1 remained at the NE in KASH1/KASH2 DN mice, whereas nesprin-1 is absent from the NE in the cells derived from the KASH1 KO or KASH1/2 DKO. [41,42]. In contrast, nuclei were properly anchored in skeletal muscle derived from KASH2 KO mice, suggesting nesprin-2 KASH-containing isoforms do not participate in myonuclear positioning [42]. Nonetheless, KASH2 may be more critical in retinal and neuronal development as there were retina and learning/memory defects in KASH2 KO mice (for further discussion the reader is referred to the section ‘OTHER NESPRIN MOUSE MODELS’) [45,48].

Nesprin-1 C-terminal KO

Global Nesprin-1 C-terminal KO line was established by deletion of the floxed 16th exon of Syne-1 gene and resulted in a premature stop codon at the 13th exon (counted backwards from the last exon) in Prof. Chen's Laboratory [49]. This KO mouse would theoretically have ablated all nesprin-1 isoforms containing the C-terminal SR region, including nesprin-1α1, nesprin-1α2 and nesprin-1β. KO litters exhibited over 60% lethality due to muscle weakness leading to feeding insufficiency [49]. The surviving KO pups displayed growth retardation and reduced exercise capacity, although their heart function was normal [49]. Furthermore, centralised nuclei were observed in the KO mouse muscle fibres [49]. Ex vivo analysis showed the expression levels of SUN1 and SUN2 were up-regulated in heart and skeletal muscle, respectively, further confirming that nesprin-1 and the LINC complex play essential roles in nuclear positioning [49].

Nesprin-1α2 KO

Global nesprin-1α2 KO mouse strain was also generated in Prof. Chen's laboratory by floxing the first unique exon of nesprin-1α2, which was then subsequently crossed with the Sox2Cre mouse to specifically knock out the nesprin-1α2 isoform that is highly expressed in skeletal and cardiac muscle [50]. The lethality was high as only 2 out of 17 litters survived. At embryonic day 18.5 (E18.5), KO mice remained cyanotic and died within 5 minutes, while WT turned pink and started to breathe [50]. Those findings strongly indicate the nesprin-1α2 is indispensable for embryonic development.

Viable KO mice were small with reduced body weight and developed kyphosis after postnatal day 21 (P21), indicating EDMD-like skeletal muscle dysfunction [50]. Nuclei clustering was observed in the tibialis anterior (TA) muscle derived from these nesprin-1α2 KO mice at E18.5, which was akin to KASH1 KO and nesprin-1 C-terminal KO mice [42,49,50]. Nesprin-1α2 KO samples displayed reduced SUN1 expression and mis-localisation of SUN1 from the NE [50]. Surprisingly, the MT motor proteins kinesin-1 including its subunits kinesin light chain-1/2 (KLC-1/2) and kinesin heavy chain kif5b were also displaced from the NE, supporting the notion of that dynamic myonuclear positioning is governed by muscle-specific isoform nesprin-1α2 and its association with kinesin-1 in vivo [50].

Other nesprin mouse models

Nesprin-1/2 mouse models with skin/retina/brain phenotypes

Nesprin-1 CH KO and Nesprin-2 CH KO

Two global nesprin-1/2 N-terminal ABD KO models exist [17,50]. Nesprin-2 ABD was knocked out by deletion of the 2nd–4th exons of the Syne-2 gene encoded for the first CH domain in nesprin-2 CH KO mice [17]. These mice were well developed and did not exhibit any skeletal muscle or heart defects [17]. However, the epidermis from these global KO mice was thicker but did not reveal gross abnormalities [17]. Isolated primary dermal fibroblasts and keratinocytes from the KO mice possessed deformed nuclei with unevenly distributed emerin, indicating disrupted NE organisation [17]. Unlike nesprin-2 CH KO mice, nesprin-1 CH KO mice were generated by floxing the 9th exon, which encodes for the second CH domain of nesprin-1 [50]. These mice developed normally without any phenotypes, and the expression levels and localisation of LINC complex components were also unchanged [50]. These two different phenotypes could be caused by the distinct functions of two CH domains. Nesprin-1 and -2 contain two CH domains (CH1 and CH2) juxtaposed at the N-terminus. A single CH2 domain is not able to bind to actin filaments, but it acts as a CH1 enhancer to strengthen the binding with F-actin [51,52]. Therefore, the function of ABD may be partially present in nesprin-1 CH KO, while ABD function was abolished in nesprin-2 CH KO mice via depletion of the CH1 domain.

Nesprin-2 KASH KO and Nesprin-1/2 KASH DKO

The global KASH2 KO mouse line generated by Professor Han's Laboratory was initially used to investigate nuclear positioning in muscle as discussed above [42]. There were no muscle defects observed, but a severe reduction in the thickness of the outer nuclear layer in the retina, resulting from the mis-localisation of photoreceptor nuclei [48]. Moreover, KASH2 KO mice showed reduced response to a maze test and abnormally active responses to new environments, indicating a memory and learning defect [45]. In addition, the homozygous/heterozygous global nesprin-1/2 KASH DKO mouse line generated by the same group showed more severe brain phenotypes: a smaller brain with enlarged lateral ventricles, inverted layers, loss of other specific cell layers and disrupted laminary structure [45]. It is intriguing that similar retinal and neuronal phenotypes were also observed in the mice with deletion of both SUN1 and SUN2 [45,48].

The three mouse lines above revealed the crucial roles of the LINC complex in retinogenesis and neurogenesis: nesprin-1/2, in particular nesprin-2 interacts with SUN1/2 to form the LINC complex, connecting the nucleus to the centrosome through interactions with MT motor proteins dynein/dynactin and kinesin, which regulates dramatic nuclear movement during interkinetic nuclear migration and/or nucleokinesis processes that are necessary for proper brain and retina development [5355].

Nesprin-2 (GFP) KASH DN

In addition to the 13 nesprin-1/2 mouse models discussed above, Hodzic's Laboratory generated a KASH2 DN mouse strain overexpressing GFP fused to the last 65 amino acids of the nesprin-2 KASH domain [5658]. It was generated using the Cre/Lox system, which allows targeted disruption of endogenous SUN/KASH interactions through the inducible expression of a recombinant KASH domain. To date, using this GFP-KASH2 DN mouse line as a genetic tool, several LINC complex disruption models were successfully established in a tissue-specific manner such as cerebellum, retina and skeletal muscle. This strategy bypasses the perinatal lethality and potential cell non-autonomous effects of other existing global nesprin-1/2 KO mouse models [38,42,49,50]. These mice robustly overexpressed nesprin-2 KASH, with mis-localisation of the endogenous nesprin to the endoplasmic reticulum (ER), leading to uncoupling of the nucleoskeleton from the cytoskeleton, which furthers our understanding of the physiological relevance of LINC complexes during development and homeostasis in a wide variety of mammalian tissues [57,58].

Nesprin-3, Nesprin-4 and KASH5 mouse models

Nesprin-3 KO mice were generated via targeted deletion of the 2nd exon, which contains the translation start site for both nesprin-3α and nesprin-3β isoforms [59]. These KO mice were indistinguishable from WT littermates. There were no overt phenotypes reported [59].

Nesprin-4 KO mice were established by replacing the 2nd to 6th exons with an IRES β-gal cassette, resulting in an effectively null allele [60]. Loss of nesprin-4 impaired localisation of nuclei from the base to apex in outer hair cells (OHC), leading to progressive hearing loss, reproducing the phenotype found in deaf patients [60].

KASH5 KO mice were generated via targeted deletion of exons 5th–8th, which resulted in a premature stop codon, leading to a complete absence of KASH5 [61]. The KASH5 KO mice were phenotypically normal except that both male and female were infertile. Testes were much smaller in males, while the ovaries were barely visible in females [61]. A potential explanation is that KASH5 associates with SUN1, indirectly coupling telomeres with the MT motor protein dynein, facilitating efficient homologous chromosome pairing during spermatogenesis [61]; thus the deficiency of KASH5 would cause the arrest of meiosis, and subsequent infertility.

Possible mechanisms underlying the phenotypes observed in nesprin mouse models

To date, the majority of nesprin variants identified in the SYNE-1 and SYNE-2 genes have been shown to contribute to pathogenesis of muscle diseases including EDMD, DCM, congenital muscular dystrophy (CMD), arthrogryposis multiplex congenita (AMC) [12,2937,62] and CNS disorders such as ARCA1, autism spectrum disorder and bipolar disorder, respectively [6369]. Nesprin-1/2 variants associated with skeletal muscle or cardiac muscle defects are heterozygous missense mutations causing amino acid substitutions and mainly localise at the C-terminus of SYNE-1/2. In this region, there is a highly conserved fragment with little secondary structure named ‘adaptive domain’ (AD). The AD together with SRs in this region help to mediate homodimerisation of nesprin proteins and bind to other LINC complex components, including lamin A/C and emerin, with high affinity [70,71]. The AD also plays roles in maintaining structural and thermodynamic properties of the nesprin proteins, which has been confirmed by thermal unfolding tests using circular dichroism and dynamic light scattering [70]. Therefore, these nesprin mutations potentially cause defects in the structure/flexibility of the functional domains binding to lamin A/C, emerin and SUN1/2. In contrast, nesprin-1/2 variants associated with CNS disorders are homozygous nonsense mutations, which scatter along SYNE-1/2 genes, especially SYNE-1, resulting in truncation of multiple nesprin isoforms (for further details the reader is referred to a recent review [72]). These two distinct types of nesprin-1/2 variants may affect tissue-specific isoforms of nesprin-1 and/or -2 and their associated LINC complexes, leading to tissue-specific diseases. In addition, only one SYNE-4 mutation causing high-frequency hearing loss was reported in two families; this phenotype has been recapitulated in nesprin-4 KO mice [60]. Therefore, most of the nesprin mouse models were generated for investigating nesprin-1/2 functions.

Out of 14 nesprin-1/2 mouse models, 10 exhibited skeletal muscle or cardiac defects, whereas 2 strains displayed CNS disorders. Although the severity of the phenotypes in affected organs/tissues are variable, they all exhibit similar cellular and molecular changes: defects in nuclear morphology, nuclear positioning and migration, abnormal localisation and binding of the LINC complex proteins SUN1/2, lamin A/C and emerin with nesprin-1/2, indicating a perturbation of the LINC complex, similar to those caused by nesprin mutations reported in the cells of patients with muscle or CNS disorders. These support two principal hypotheses underlying nesprin-related diseases: structural disruption and gene dysregulation.

Evidence for structural hypothesis

Studies on patient tissues/cells carrying nesprin-1/2 mutations revealed structural pathological changes. Muscle biopsies derived from EDMD patients carrying nesprin-1/2 mutations exhibited centralised nuclei with increased variability of fibre size [31,34]. Further studies demonstrated cellular changes with misshapen nuclei, invaginated and detached NE, and reduced heterochromatin density in EDMD and AMC patient cells carrying nesprin-1/2 mutations [12,37]. In agreement with these observed changes in patient samples, 10 nesprin-1/2 mouse models exhibited either mis-positioning of non-synaptic and synaptic nuclei in skeletal muscle or reduced distance between adjacent nuclei, or elongated nuclei in cardiac muscle, while 2 strains (nesprin-2 KASH KO and nesprin-1/2 KASH DKO) revealed the defect in neuronal migration [29,38,4042,49,50]. Furthermore, LINC complex components lamin A/C, emerin and/or SUN1/2 were mis-localised from the NE and their interactions with nesprin-1/2 were altered [12,30,38,40,50]. The findings strongly suggest that nesprin-1/2 mutations cause major disruption in the integrity of the LINC complex and uncouple the nucleoskeleton from the cytoskeleton, resulting in fragile nuclei. This was particularly striking in skeletal and cardiac muscle when subjected to mechanical strain, which consequently affected nuclear migration and positioning as these process required substantial cytoskeletal forces acting on the nucleus via an intact LINC complex.

Pioneering insights into the function of the LINC complex in nuclear migration and positioning came from studying nesprin-1/2 in lower organisms. Depletion of the Drosophila nesprin orthologue MSP-300 resulted in defective muscle/tendon connections and mis-localised nuclei in oocyte cells [73]. Mutations in C. elegans ANC-1, a single giant ONM nesprin orthologue, also led to a muscle defect due to disrupted myonuclear migration and decoupled mitochondria from the actin cytoskeleton [74]. Indeed, emerging evidence has further revealed that functions of the LINC complex in nuclear migration are evolutionarily conserved in mammals. In both muscle and CNS, nesprin-1/2 act as a hub to assemble the system required for nuclear movement through their interactions with SUN1/2 via their KASH domains to form the LINC complex at the NE, and also bind to the MT motor proteins dynein/dynactin and kinesin via their SRs [18,45,75]. Recently, a ‘LEWD’ motif at the C-terminus of nesprin-1/2 has been identified as a binding region for motor proteins kinesin-1 and C-terminal SRs of C. elegans UNC-83, nesprin orthologue, for dynein [18,30,76]. Therefore, nuclei can ‘walk’ bi-directionally along the MT-LINC complex that surrounds the NE to achieve precisely nuclear migration and positioning in myoblasts/myotubes and neuronal progenitors/neurons and promote muscle and CNS development [18,45]. In addition, centrosomal proteins Akap450, pericentriolar material-1 (PCM-1) and pericentrin, components of the microtubule-organising centre (MTOC), have recently been shown to relocalise to the NE, participating in MT nucleation at the initial stage of muscle cell differentiation in a nesprin-1α-dependent manner [19,77].

Evidence for gene dysregulation hypothesis

LINC complex mediates mechanotransduction events, translating biophysical forces into biochemical signalling that regulates gene expression. Several studies have now confirmed that the nesprin giant proteins are subjected to mechanical tension and that physical forces transmitted across the LINC complex regulate recruitment of lamin A/C to the INM and emerin phosphorylation [78,79]. These two LINC complex-associated components have also been shown to anchor chromatin via direct interactions with histones or other chromatin-associated proteins, such as heterochromatin protein 1 (HP1) and lamin B receptor (LBR) for lamin A/C and barrier-to-autointegration factor (BAF) for emerin. These interactions are essential for genome arrangement and gene expression [8083]. Moreover, various transcriptional factors have been reported as binding partners for the LINC complex components including extracellular signal-regulated kinase (ERK) 1/2 and α-catenin for nesprin-2, retinoblastoma protein (pRb), c-fos and ERK1/2 for lamin A/C [8487]. Interestingly, several recent studies demonstrated that nesprin mutations result in gene dysregulation. Firstly, enhanced ERK1/2 activity was observed in nesprin-1 KASH KO heart tissue, fibroblasts derived from EDMD-DCM patients and nesprin-1 mutant-transfected cells, which might contribute to aberrant activation and expression of downstream genes encoding for the components of muscle fibre and sarcomere, thus contributing to muscle dysfunction [30]. Secondly, impaired response to mechanical stress was reported in CMs isolated from KASH1/2 DKO mice, which showed completely blunted response in biomechanical genes [40]. Finally, either myoblasts derived from EDMD patients or C2C12 myoblasts infected with nesprin-1 mutations identified in DCM patients exhibited perturbed myogenesis with less-defined myotube structure or reduced expression of myogenic transcriptional factors, such as myoD, myogenin and myosin heavy chain [12,30]. Further investigation is required to elucidate the mechanisms between LINC complex disruption and the observed gene dysregulation.

In summary, both structural and gene regulation hypotheses are not mutually exclusive. It is not clear which, if either, is the key trigger. We propose a potential mechanism whereby nesprin mutations may fail to build a functional scaffold and/or to maintain chromatin compartmentalisation with other LINC complex components such as SUN1/2, emerin and lamin A/C, leading to reduced heterochromatin and defective compartmentalisation; potentially it causes defects in initiation of the gene transcription process, resulting in decreased or delayed expression of the genes encoding proteins that are critical for structural integrity or participating in regulating cell activities such as cell differentiation, migration and division, thus accelerating pathogenesis and driving the onset of diseases.

Concluding remarks

Seventeen various nesprin mouse models have generated valuable information regarding the roles of nesprins and the LINC complex in anchoring the nucleus to cytoskeletal networks, nuclear positioning and migration, especially in muscle cells. However, questions regarding how disruption of the LINC complex caused by nesprin mutants leads to changes in structural, cell signalling and gene expression, contributing to pathogenesis of nesprin-related diseases remain unanswered.

Further knowledge is required to better understand the diverse spectrum of nesprin isoforms. Moreover, full characterisation of tissues or cells derived from patients with EDMD, DCM or ARCA1 etc., and introduced pluripotent stem cells (iPSCs) will help to decipher the roles of nesprins in developmental cell fate and physiological functions of disease-relevant cells [88]. Furthermore, in contrast with current nesprin mouse models with deletion or overexpression of functional domains (KASH domains, C-terminal SRs and CH domains), more clinically relevant mouse models could be generated to recapitulate the human conditions via CRISPR Cas9 genome-edited knock-in mouse lines, or focus on functional studies on tissue-specific nesprin isoforms such as nesprin-1α2, 2α1 and 2εƐ2 in heart and skeletal muscle, and two nesprin-1 KASH-less isoforms in brain [9,49,89]. In addition, whole-genome or single cell microarray analysis could be performed on cells isolated from these models to explore the expression profiles of dysregulated genes and associated signalling pathways. These approaches would potentially help uncover how dysfunction of nesprins and the LINC complex contribute to pathogenesis of nesprin-related diseases and provide information on establishing therapeutic targets for these disorders.

Abbreviations

     
  • ABD

    actin-binding domain

  •  
  • AD

    adaptive domain

  •  
  • AMC

    arthrogryposis multiplex congenita

  •  
  • ARCA1

    autosomal recessive cerebellar ataxia type 1

  •  
  • CH

    Calponin Homology

  •  
  • CMs

    Cardiomyocytes

  •  
  • CNS

    central nervous system

  •  
  • DCM

    dilated cardiomyopathy

  •  
  • DKO

    double KO

  •  
  • DN

    dominant negative

  •  
  • EDMD

    Dreifuss muscular dystrophy

  •  
  • INM

    inner nuclear membrane

  •  
  • KO

    knockout

  •  
  • LINC

    LInker of Nucleoskeleton-and-Cytoskeleton

  •  
  • LRMP

    lymphoid-restricted membrane protein

  •  
  • LV

    left ventricle

  •  
  • MCK

    muscle creatine kinase

  •  
  • MT

    microtubule

  •  
  • NE

    nuclear envelope

Funding

This work was supported by the British Heart Foundation (BHF) [PG/11/58/29004 to Q.P.Z., RG/11/14/29056 to C.M.S.] and the National Natural Science Foundation of China [81270289 to L.R.].

Acknowledgments

We thank Dr. Andrew Cobb (King's College London) for a critical reading of this manuscript.

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

References

References
1
Zhang
,
Q.
,
Skepper
,
J.N.
,
Yang
,
F.
,
Davies
,
J.D.
,
Hegyi
,
L.
,
Roberts
,
R.G.
et al. 
(
2001
)
Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues
.
J. Cell Sci.
114
(
Pt 24
),
4485
4498
PMID:
[PubMed]
2
Zhang
,
Q.
,
Ragnauth
,
C.D.,
Skepper
,
J.N.
,
Worth
,
N.F.
,
Warren
,
D.T.
,
Roberts
,
R.G.
et al. 
(
2005
)
Nesprin-2 is a multi-isomeric protein that binds lamin and emerin at the nuclear envelope and forms a subcellular network in skeletal muscle
.
J. Cell Sci.
118
(
Pt 4
),
673
687
3
Wilhelmsen
,
K.
,
Litjens
,
S.H.M.
,
Kuikman
,
I.
,
Tshimbalanga
,
N.
,
Janssen
,
H.
,
van den Bout
,
I.
et al. 
(
2005
)
Nesprin-3, a novel outer nuclear membrane protein, associates with the cytoskeletal linker protein plectin
.
J. Cell Biol.
171
,
799
810
4
Roux
,
K.J.
,
Crisp
,
M.L.
,
Liu
,
Q.
,
Kim
,
D.
,
Kozlov
,
S.
,
Stewart
,
C.L.
et al. 
(
2009
)
Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization
.
Proc. Natl Acad. Sci. U.S.A.
106
,
2194
2199
5
Behrens
,
T.W.
,
Jagadeesh
,
J.
,
Scherle
,
P.
,
Kearns
,
G.
,
Yewdell
,
J.
and
Staudt
,
L.M.
(
1994
)
Jaw1, A lymphoid-restricted membrane protein localized to the endoplasmic reticulum
.
J. Immunol.
153
,
682
690
PMID:
[PubMed]
6
Morimoto
,
A.
,
Shibuya
,
H.
,
Zhu
,
X.
,
Kim
,
J.
,
Ishiguro
,
K.
,
Han
,
M.
et al. 
(
2012
)
A conserved KASH domain protein associates with telomeres, SUN1, and dynactin during mammalian meiosis
.
J. Cell Biol.
198
,
165
172
7
Rajgor
,
D.
,
Mellad
,
J.A.
,
Autore
,
F.
,
Zhang
,
Q.
,
Shanahan
,
C.M.
and
Sharma
,
K.
(
2012
)
Multiple novel nesprin-1 and nesprin-2 variants act as versatile tissue-specific intracellular scaffolds
.
PLoS ONE
7
,
e40098
8
Rajgor
,
D.
and
Shanahan
,
C.M.
(
2013
)
Nesprins: from the nuclear envelope and beyond
.
Expert Rev. Mol. Med.
15
,
e5
9
Duong
,
N.T.
,
Morris
,
G.E.
,
Lam
,
L.T.
,
Zhang
,
Q.
,
Sewry
,
C.A.
,
Shanahan
,
C.M.
et al. 
(
2014
)
Nesprins: tissue-specific expression of epsilon and other short isoforms
.
PLoS ONE
9
,
e94380
10
Holt
,
I.
,
Duong
,
N.T.
,
Zhang
,
Q.
,
Lam
,
L.T.
,
Sewry
,
C.A.
,
Mamchaoui
,
K.
et al. 
(
2016
)
Specific localization of nesprin-1-alpha2, the short isoform of nesprin-1 with a KASH domain, in developing, fetal and regenerating muscle, using a new monoclonal antibody
.
BMC Cell Biol.
17
,
26
11
Haque
,
F.
,
Mazzeo
,
D.
,
Patel
,
J.T.
,
Smallwood
,
D.T.
,
Ellis
,
J.A.
,
Shanahan
,
C.M.
et al. 
(
2010
)
Mammalian SUN protein interaction networks at the inner nuclear membrane and their role in laminopathy disease processes
.
J. Biol. Chem.
285
,
3487
3498
12
Zhang
,
Q.
,
Bethmann
,
C.
,
Worth
,
N.F.
,
Davies
,
J.D.
,
Wasner
,
C.
,
Feuer
,
A.
et al. 
(
2007
)
Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity
.
Hum. Mol. Genet.
16
,
2816
2833
13
Yang
,
L.
,
Munck
,
M.
,
Swaminathan
,
K.
,
Kapinos
,
L.E.
,
Noegel
,
A.A.
,
Neumann
,
S.
et al. 
(
2013
)
Mutations in LMNA modulate the lamin A--Nesprin-2 interaction and cause LINC complex alterations
.
PLoS ONE
8
,
e71850
14
Sosa
,
B.A.
,
Rothballer
,
A.
,
Kutay
,
U.
and
Schwartz
,
T.U.
(
2012
)
LINC complexes form by binding of three KASH peptides to domain interfaces of trimeric SUN proteins
.
Cell
149
,
1035
1047
15
Sosa
,
B.A.
,
Kutay
,
U.
and
Schwartz
,
T.U.
(
2013
)
Structural insights into LINC complexes
.
Curr. Opin. Struct. Biol.
23
,
285
291
16
Zhen
,
Y.Y.
,
Libotte
,
T.
,
Munck
,
M.
,
Noegel
,
A.A.
and
Korenbaum
,
E.
(
2002
)
NUANCE, a giant protein connecting the nucleus and actin cytoskeleton
.
J. Cell Sci.
115
(
Pt 15
),
3207
3222
PMID:
[PubMed]
17
Luke
,
Y.
,
Zaim
,
H.
,
Karakesisoglou
,
I.
,
Jaeger
,
V.M.
,
Sellin
,
L.
,
Lu
,
W.
et al. 
(
2008
)
Nesprin-2 Giant (NUANCE) maintains nuclear envelope architecture and composition in skin
.
J. Cell Sci.
121
,
1887
1898
18
Wilson
,
M.H.
and
Holzbaur
,
E.L.
(
2015
)
Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells
.
Development
142
,
218
228
19
Gimpel
,
P.
,
Lee
,
Y.L.
,
Sobota
,
R.M.
,
Calvi
,
A.
,
Koullourou
,
V.
,
Patel
,
R.
et al. 
(
2017
)
Nesprin-1alpha-dependent microtubule nucleation from the nuclear envelope via Akap450 is necessary for nuclear positioning in muscle cells
.
Curr. Biol.
27
,
2999
3009.e9
20
Crisp
,
M.
,
Liu
,
Q.
,
Roux
,
K.
,
Rattner
,
J.B.
,
Shanahan
,
C.
,
Burke
,
B.
et al. 
(
2006
)
Coupling of the nucleus and cytoplasm: role of the LINC complex
.
J. Cell Biol.
172
,
41
53
21
Mellad
,
J.A.
,
Warren
,
D.T.
and
Shanahan
,
C.M.
(
2011
)
Nesprins LINC the nucleus and cytoskeleton
.
Curr. Opin. Cell Biol.
23
,
47
54
22
Ketema
,
M.
,
Wilhelmsen
,
K.
,
Kuikman
,
I.
,
Janssen
,
H.
,
Hodzic
,
D.
and
Sonnenberg
,
A.
(
2007
)
Requirements for the localization of nesprin-3 at the nuclear envelope and its interaction with plectin
.
J. Cell Sci.
120
(
Pt 19
),
3384
3394
23
Morgan
,
J.T.
,
Pfeiffer
,
E.R.
,
Thirkill
,
T.L.
,
Kumar
,
P.
,
Peng
,
G.
and
Fridolfsson
,
H.N.
(
2011
)
Nesprin-3 regulates endothelial cell morphology, perinuclear cytoskeletal architecture, and flow-induced polarization
.
Mol. Biol. Cell
22
,
4324
4334
24
Lindeman
,
R.E.
and
Pelegri
,
F.
(
2012
)
Localized products of futile cycle/lrmp promote centrosome-nucleus attachment in the zebrafish zygote
.
Curr. Biol.
22
,
843
851
25
Shindo
,
Y.
,
Kim
,
M.-R.
,
Miura
,
H.
,
Yuuki
,
T.
,
Kanda
,
T.
,
Hino
,
A.
et al. 
(
2010
)
Lrmp/Jaw1 is expressed in sweet, bitter, and umami receptor-expressing cells
.
Chem. Senses
35
,
171
177
26
Lee
,
C.Y.
,
Horn
,
H.F.
,
Stewart
,
C.L.
,
Burke
,
B.
,
Bolcun-Filas
,
E.
,
Schimenti
,
J.C.
et al. 
(
2015
)
Mechanism and regulation of rapid telomere prophase movements in mouse meiotic chromosomes
.
Cell Rep.
11
,
551
563
27
Gough
,
L.L.
,
Fan
,
J.
,
Chu
,
S.
,
Winnick
,
S.
and
Beck
,
K.A.
(
2003
)
Golgi localization of Syne-1
.
Mol. Biol. Cell.
14
,
2410
2424
28
Warren
,
D.T.
,
Tajsic
,
T.
,
Mellad
,
J.A.
,
Searles
,
R.
,
Zhang
,
Q.
and
Shanahan
,
C.M.
(
2010
)
Novel nuclear nesprin-2 variants tether active extracellular signal-regulated MAPK1 and MAPK2 at promyelocytic leukemia protein nuclear bodies and act to regulate smooth muscle cell proliferation
.
J. Biol. Chem.
285
,
1311
1320
29
Puckelwartz
,
M.J.
,
Kessler
,
E.J.
,
Kim
,
G.
,
DeWitt
,
M.M.
,
Zhang
,
Y.
,
Earley
,
J.U.
et al. 
(
2010
)
Nesprin-1 mutations in human and murine cardiomyopathy
.
J. Mol. Cell Cardiol.
48
,
600
608
30
Zhou
,
C.
,
Li
,
C.
,
Zhou
,
B.
,
Sun
,
H.
,
Koullourou
,
V.
,
Holt
,
I.
et al. 
(
2017
)
Novel nesprin-1 mutations associated with dilated cardiomyopathy cause nuclear envelope disruption and defects in myogenesis
.
Hum. Mol. Genet.
26
,
2258
2276
31
Chen
,
Z.
,
Ren
,
Z.
,
Mei
,
W.
,
Ma
,
Q.
,
Shi
,
Y.
,
Zhang
,
Y.
et al. 
(
2017
)
A novel SYNE1 gene mutation in a Chinese family of Emery-Dreifuss muscular dystrophy-like
.
BMC Med. Genet.
18
,
63
32
Haskell
,
G.T.
,
Jensen
,
B.C.
,
Samsa
,
L.A.
,
Marchuk
,
D.
,
Huang
,
W.
,
Skrzynia
,
C.
et al. 
(
2017
)
Whole exome sequencing identifies truncating variants in nuclear envelope genes in patients with cardiovascular disease
.
Circ. Cardiovasc. Genet.
10
,
e001443
33
Akinrinade
,
O.
,
Ollila
,
L.
,
Vattulainen
,
S.
,
Tallila
,
J.
,
Gentile
,
M.
,
Salmenperä
,
P.
et al. 
(
2015
)
Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy
.
Eur. Heart J.
36
,
2327
2337
34
Fanin
,
M.
,
Savarese
,
M.
,
Nascimbeni
,
A.C.
,
Di Fruscio
,
G.
,
Pastorello
,
E.
,
Tasca
,
E.
et al. 
(
2015
)
Dominant muscular dystrophy with a novel SYNE1 gene mutation
.
Muscle Nerve
51
,
145
147
35
Voit
,
T.
,
Cirak
,
S.
,
Abraham
,
S.
,
Karakesisoglou
,
I.
,
Parano
,
E.
,
Pavone
,
P.
et al. 
(
2007
)
C.O.4 Congenital muscular dystrophy with adducted thumbs, mental retardation, cerebellar hypoplasia and cataracts is caused by mutation of Enaptin (Nesprin-1): The third nuclear envelopathy with muscular dystrophy
.
Neuromuscul. Disord.
17
,
833
834
36
Attali
,
R.
,
Warwar
,
N.
,
Israel
,
A.
,
Gurt
,
I.
,
McNally
,
E.
,
Puckelwartz
,
M.
et al. 
(
2009
)
Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis
.
Hum. Mol. Genet.
18
,
3462
3469
37
Baumann
,
M.
,
Steichen-Gersdorf
,
E.
,
Krabichler
,
B.
,
Petersen
,
B.-S.
,
Weber
,
U.
,
Schmidt
,
W.M.
et al. 
(
2017
)
Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation
.
Eur. J. Hum. Genet.
25
,
262
266
38
Puckelwartz
,
M.J.
,
Kessler
,
E.
,
Zhang
,
Y.
,
Hodzic
,
D.
,
Randles
,
K.N.
,
Morris
,
G.
et al. 
(
2009
)
Disruption of nesprin-1 produces an Emery Dreifuss muscular dystrophy-like phenotype in mice
.
Hum. Mol. Genet.
18
,
607
620
39
van Berlo
,
J.H.
,
de Voogt
,
W.G.
,
van der Kooi
,
A.J.
,
van Tintelen
,
J.P.
,
Bonne
,
G.
,
Yaou
,
R.B.
et al. 
(
2005
)
Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death?
J. Mol. Med. (Berl).
83
,
79
83
40
Banerjee
,
I.
,
Zhang
,
J.
,
Moore-Morris
,
T.
,
Pfeiffer
,
E.
,
Buchholz
,
K.S.
,
Liu
,
A.
et al. 
(
2014
)
Targeted ablation of nesprin 1 and nesprin 2 from murine myocardium results in cardiomyopathy, altered nuclear morphology and inhibition of the biomechanical gene response
.
PLoS Genet.
10
,
e1004114
41
Grady
,
R.M.
,
Starr
,
D.A.
,
Ackerman
,
G.L.
,
Sanes
,
J.R.
and
Han
,
M.
(
2005
)
Syne proteins anchor muscle nuclei at the neuromuscular junction
.
Proc. Natl Acad. Sci. U.S.A.
102
,
4359
4364
42
Zhang
,
X.
,
Xu
,
R.
,
Zhu
,
B.
,
Yang
,
X.
,
Ding
,
X.
,
Duan
,
S.
et al. 
(
2007
)
Syne-1 and Syne-2 play crucial roles in myonuclear anchorage and motor neuron innervation
.
Development
134
,
901
908
43
Johnson
,
J.E.
,
Wold
,
B.J.
and
Hauschka
,
S.D.
(
1989
)
Muscle creatine kinase sequence elements regulating skeletal and cardiac muscle expression in transgenic mice
.
Mol. Cell Biol.
9
,
3393
3399
PMID:
[PubMed]
44
Baird
,
M.F.
,
Graham
,
S.M.
,
Baker
,
J.S.
and
Bickerstaff
,
G.F.
(
2012
)
Creatine-kinase- and exercise-related muscle damage implications for muscle performance and recovery
.
J. Nutr. Metab.
2012
,
960363
45
Zhang
,
X.
,
Lei
,
K.
,
Yuan
,
X.
,
Wu
,
X.
,
Zhuang
,
Y.
,
Xu
,
T.
et al. 
(
2009
)
SUN1/2 and Syne/Nesprin-1/2 complexes connect centrosome to the nucleus during neurogenesis and neuronal migration in mice
.
Neuron
64
,
173
187
46
Mitzner
,
W.
,
Blosser
,
S.
,
Yager
,
D.
and
Wagner
,
E.
(
1992
)
Effect of bronchial smooth muscle contraction on lung compliance
.
J. Appl. Physiol. (1985)
72
,
158
167
47
Merrell
,
A.J.
and
Kardon
,
G.
(
2013
)
Development of the diaphragm-a skeletal muscle essential for mammalian respiration
.
FEBS J.
280
,
4026
4035
48
Yu
,
J.
,
Lei
,
K.
,
Zhou
,
M.
,
Craft
,
C.M.
,
Xu
,
G.
,
Xu
,
T.
et al. 
(
2011
)
KASH protein Syne-2/Nesprin-2 and SUN proteins SUN1/2 mediate nuclear migration during mammalian retinal development
.
Hum. Mol. Genet.
20
,
1061
1073
49
Zhang
,
J.
,
Felder
,
A.
,
Liu
,
Y.
,
Guo
,
L.T.
,
Lange
,
S.
,
Dalton
,
N.D.
et al. 
(
2010
)
Nesprin 1 is critical for nuclear positioning and anchorage
.
Hum. Mol. Genet.
19
,
329
341
50
Stroud
,
M.J.
,
Feng
,
W.
,
Zhang
,
J.
,
Veevers
,
J.
,
Fang
,
X.
,
Gerace
,
L.
et al. 
(
2017
)
Nesprin 1alpha2 is essential for mouse postnatal viability and nuclear positioning in skeletal muscle
.
J. Cell Biol.
216
,
1915
1924
51
Winder
,
S.J.
,
Hemmings
,
L.
,
Maciver
,
S.K.
,
Bolton
,
S.J.
,
Tinsley
,
J.M.
et al. 
Davies
,
K.E.
et al. 
(
1995
)
Utrophin actin binding domain: analysis of actin binding and cellular targeting
.
J. Cell Sci.
108
(
Pt 1
),
63
71
PMID:
[PubMed]
52
Djinovic Carugo
,
K.
,
Banuelos
,
S.
and
Saraste
,
M.
(
1997
)
Crystal structure of a calponin homology domain
.
Nat. Struct. Biol.
4
,
175
179
53
Kosodo
,
Y.
,
Suetsugu
,
T.
,
Suda
,
M.
,
Mimori-Kiyosue
,
Y.
,
Toida
,
K.
,
Baba
,
S.A.
et al. 
(
2011
)
Regulation of interkinetic nuclear migration by cell cycle-coupled active and passive mechanisms in the developing brain
.
EMBO J.
30
,
1690
1704
54
Wynshaw-Boris
,
A.
(
2007
)
Lissencephaly and LIS1: insights into the molecular mechanisms of neuronal migration and development
.
Clin. Genet.
72
,
296
304
55
Baye
,
L.M.
and
Link
,
B.A.
(
2008
)
Nuclear migration during retinal development
.
Brain Res.
1192
,
29
36
56
Razafsky
,
D.
,
Blecher
,
N.
,
Markov
,
A.
,
Stewart-Hutchinson
,
P.J.
and
Hodzic
,
D.
(
2012
)
LINC complexes mediate the positioning of cone photoreceptor nuclei in mouse retina
.
PLoS ONE
7
,
e47180
57
Razafsky
,
D.
and
Hodzic
,
D.
(
2014
)
Temporal and tissue-specific disruption of LINC complexes in vivo
.
Genesis
52
,
359
365
58
Razafsky
,
D.
,
Potter
,
C.
and
Hodzic
,
D.
(
2015
)
Validation of a mouse model to disrupt LINC complexes in a cell-specific manner
.
J. Vis. Exp.
e53318
59
Ketema
,
M.
,
Kreft
,
M.
,
Secades
,
P.
,
Janssen
,
H.
and
Sonnenberg
,
A.
(
2013
)
Nesprin-3 connects plectin and vimentin to the nuclear envelope of Sertoli cells but is not required for Sertoli cell function in spermatogenesis
.
Mol. Biol. Cell
24
,
2454
2466
60
Horn
,
H.F.
,
Brownstein
,
Z.
,
Lenz
,
D.R.
,
Shivatzki
,
S.
,
Dror
,
A.A.
,
Dagan-Rosenfeld
,
O.
et al. 
(
2013
)
The LINC complex is essential for hearing
.
J. Clin. Invest.
123
,
740
750
61
Horn
,
H.F.
,
Kim
,
D.I.
,
Wright
,
G.D.
,
Wong
,
E.S.M.
,
Stewart
,
C.L.
,
Burke
,
B.
et al. 
(
2013
)
A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton
.
J. Cell Biol.
202
,
1023
1039
62
Laquerriere
,
A.
,
Maluenda
,
J.
,
Camus
,
A.
,
Fontenas
,
L.
,
Dieterich
,
K.
,
Nolent
,
F.
et al. 
(
2014
)
Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects
.
Hum. Mol. Genet.
23
,
2279
2289
63
Gros-Louis
,
F.
,
Dupré
,
N.
,
Dion
,
P.
,
Fox
,
M.A
,
Laurent
,
S.
,
Verreault
,
S.
et al. 
(
2007
)
Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia
.
Nat. Genet.
39
,
80
85
64
Noreau
,
A.
,
Bourassa
,
C.V.
,
Szuto
,
A.
,
Levert
,
A.
,
Dobrzeniecka
,
S.
and
Gauthier
,
J.
et al. 
(
2013
)
SYNE1 mutations in autosomal recessive cerebellar ataxia
.
JAMA Neurol.
70
,
1296
1301
PMID:
[PubMed]
65
Izumi
,
Y.
,
Miyamoto
,
R.
,
Morino
,
H.
,
Yoshizawa
,
A.
,
Nishinaka
,
K.
,
Udaka
,
F.
et al. 
(
2013
)
Cerebellar ataxia with SYNE1 mutation accompanying motor neuron disease
.
Neurology
80
,
600
601
66
Synofzik
,
M.
,
Smets
,
K.
,
Mallaret
,
M.
,
Di Bella
,
D.
,
Gallenmüller
,
C.
,
Baets
,
J.
et al. 
(
2016
)
SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study
.
Brain
139
(
Pt 5
),
1378
1393
67
O'Roak
,
B.J.
,
Deriziotis
,
P.
,
Lee
,
C.
,
Vives
,
L.
,
Schwartz
,
J.J.
,
Girirajan
,
S.
et al. 
(
2011
)
Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations
.
Nat. Genet.
43
,
585
589
68
Yu
,
T.W.
,
Chahrour
,
M.H.
,
Coulter
,
M.E.
,
Jiralerspong
,
S.
,
Okamura-Ikeda
,
K.
,
Ataman
,
B.
et al. 
(
2013
)
Using whole-exome sequencing to identify inherited causes of autism
.
Neuron
77
,
259
273
69
Green
,
E.K.
,
Grozeva
,
D.
,
Forty
,
L.
,
Gordon-Smith
,
K.
,
Russell
,
E.
,
Farmer
,
A.
et al. 
(
2013
)
Association at SYNE1 in both bipolar disorder and recurrent major depression
.
Mol. Psychiatry
18
,
614
617
70
Zhong
,
Z.
,
Chang
,
S.A.
,
Kalinowski
,
A.
,
Wilson
,
K.L.
and
Dahl
,
K.N.
(
2010
)
Stabilization of the spectrin-like domains of nesprin-1alpha by the evolutionarily conserved “adaptive” domain
.
Cell. Mol. Bioeng.
3
,
139
150
71
Mislow
,
J.M.
,
Holaska
,
J.M.
,
Kim
,
M.S.
,
Lee
,
K.K.
,
Segura-Totten
,
M.
,
Wilson
,
K.L.
et al. 
(
2002
)
Nesprin-1alpha self-associates and binds directly to emerin and lamin A in vitro
.
FEBS Lett.
525
,
135
140
72
Zhou
,
C.
,
Rao
,
L.
,
Shanahan
,
C.M.
and
Zhang
,
Q.
(
2018
)
Nesprin-1/2: roles in nuclear envelope organisation, myogenesis and muscle disease
.
Biochem. Soc. Trans.
46
,
311
320
73
Rosenberg-Hasson
,
Y.
,
Renert-Pasca
,
M.
and
Volk
,
T.
(
1996
)
A Drosophila dystrophin-related protein, MSP-300, is required for embryonic muscle morphogenesis
.
Mech. Dev.
60
,
83
94
74
Starr
,
D.A.
and
Han
,
M.
(
2002
)
Role of ANC-1 in tethering nuclei to the actin cytoskeleton
.
Science
298
,
406
409
75
Razafsky
,
D.
,
Wirtz
,
D.
and
Hodzic
,
D.
(
2014
)
Nuclear envelope in nuclear positioning and cell migration
.
Adv. Exp. Med. Biol.
773
,
471
490
76
Fridolfsson
,
H.N.
and
Starr
,
D.A.
(
2010
)
Kinesin-1 and dynein at the nuclear envelope mediate the bidirectional migrations of nuclei
.
J. Cell Biol.
191
,
115
128
77
Espigat-Georger
,
A.
,
Dyachuk
,
V.
,
Chemin
,
C.
,
Emorine
,
L.
and
Merdes
,
A.
(
2016
)
Nuclear alignment in myotubes requires centrosome proteins recruited by nesprin-1
.
J. Cell Sci.
129
,
4227
4237
78
Guilluy
,
C.
,
Osborne
,
L.D.
,
Van Landeghem
,
L.
,
Sharek
,
L.
,
Superfine
,
R.
,
Garcia-Mata
,
R.
et al. 
(
2014
)
Isolated nuclei adapt to force and reveal a mechanotransduction pathway in the nucleus
.
Nat. Cell Biol.
16
,
376
381
79
Arsenovic
,
P.T.
,
Ramachandran
,
I.
,
Bathula
,
K.
,
Zhu
,
R.
,
Narang
,
J.D.
,
Noll
,
N.A.
et al. 
(
2016
)
Nesprin-2G, a component of the nuclear LINC complex, is subject to myosin-dependent tension
.
Biophys. J.
110
,
34
43
80
Stierle
,
V.
,
Couprie
,
J.
,
Östlund
,
C.
,
Krimm
,
I.
,
Zinn-Justin
,
S.
,
Hossenlopp
,
P.
et al. 
(
2003
)
The carboxyl-terminal region common to lamins A and C contains a DNA binding domain
.
Biochemistry
42
,
4819
4828
81
Taniura
,
H.
,
Glass
,
C.
and
Gerace
,
L.
(
1995
)
A chromatin binding site in the tail domain of nuclear lamins that interacts with core histones
.
J. Cell Biol.
131
,
33
44
82
Olins
,
A.L.
,
Rhodes
,
G.
,
Welch
,
D.B.M.
,
Zwerger
,
M.
and
Olins
,
D.E.
(
2010
)
Lamin B receptor: multi-tasking at the nuclear envelope
.
Nucleus
1
,
53
70
83
Lee
,
K.K.
,
Haraguchi
,
T.
,
Lee
,
R.S.
,
Koujin
,
T.
,
Hiraoka
,
Y.
and
Wilson
,
K.L.
(
2001
)
Distinct functional domains in emerin bind lamin A and DNA-bridging protein BAF
.
J. Cell Sci.
114
(
Pt 24
),
4567
4573
PMID:
[PubMed]
84
Warren
,
D.T.
,
Tajsic
,
T.
,
Porter
,
L.J.
,
Minaisah
,
R.M.
,
Cobb
,
A.
,
Jacob
,
A.
et al. 
(
2015
)
Nesprin-2-dependent ERK1/2 compartmentalisation regulates the DNA damage response in vascular smooth muscle cell ageing
.
Cell Death Differ.
22
,
1540
1550
85
Neumann
,
S.
,
Schneider
,
M.
,
Daugherty
,
R.L.
,
Gottardi
,
C.J.
,
Eming
,
S.A.
,
Beijer
,
A.
et al. 
(
2010
)
Nesprin-2 interacts with {alpha}-catenin and regulates Wnt signaling at the nuclear envelope
.
J. Biol. Chem.
285
,
34932
34938
86
Ozaki
,
T.
,
Saijo
,
M.
,
Murakami
,
K.
,
Enomoto
,
H.
,
Taya
,
Y.
and
Sakiyama
,
S.
(
1994
)
Complex formation between lamin A and the retinoblastoma gene product: identification of the domain on lamin A required for its interaction
.
Oncogene
9
,
2649
2653
PMID:
[PubMed]
87
González
,
J.M.
,
Navarro-Puche
,
A.
,
Casar
,
B.
,
Crespo
,
P.
and
Andrés
,
V.
(
2008
)
Fast regulation of AP-1 activity through interaction of lamin A/C, ERK1/2, and c-Fos at the nuclear envelope
.
J. Cell Biol.
183
,
653
666
88
Hockemeyer
,
D.
and
Jaenisch
,
R.
(
2016
)
Induced pluripotent stem cells meet genome editing
.
Cell Stem Cell
18
,
573
586
89
Razafsky
,
D.
and
Hodzic
,
D.
(
2015
)
A variant of Nesprin1 giant devoid of KASH domain underlies the molecular etiology of autosomal recessive cerebellar ataxia type I
.
Neurobiol. Dis.
78
,
57
67