Motoneurons are made in excess throughout development. Initial analysis of the mechanisms that lead to apoptotic cell death during later stages of development and the early postnatal period led to the discovery of neurotrophic factors. These factors comprise different families acting through different tyrosine kinase receptors. Intracellular signalling cascades that lead to the survival of neurons are, on the one hand, the Ras/Raf (Ras-activated factor)/MAPK (mitogen-activated protein kinase) pathway and, on the other, the PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B) pathway. The initial thought of these factors acting as single molecules in separate cascades has been converted into a model in which the dynamics of interaction of these pathways and the subcellular diverse functions of the key regulators have been taken into account. Bag1 (Bcl-2-associated athanogene 1), a molecule that was originally found to act as a co-chaperone of Hsp70 (heat-shock protein 70), also interacts with B-Raf, C-Raf and Akt to phosphorylate Bad (Bcl-2/Bcl-XL-antagonist, causing cell death), a pro-apoptotic member of the Bcl-2 family, and leads to specific subcellular distribution of phosphorylated Akt and B-Raf. These functions lead to survival of embryonic neural stem cells and therefore serve as a key event to regulate the viability of these cells.

One of the most interesting cell types of the body are motoneurons. They are made in excess in embryonic development [1]. Approx. 50% of all initially made motoneurons die by apoptosis during naturally occurring embryonic motoneuron cell death [2,3]. Furthermore, a main characteristic of acute and chronic neurodegenerative diseases such as Morbus Parkinson, amyotrophic lateral sclerosis or multiple sclerosis is defined by axonal degeneration following neuronal cell death [4]. The question of why and how neurons die is not fully understood, but it has been shown that neurons, like other cell types, need trophic support for their survival [5]. We know that neurons, whether they are of sensory or motor origin, survive independently only in the presence of neurotrophic factors. These neurotrophic factors comprise different families [2]. They belong to the neurotrophins, like BDNF (brain-derived neurotrophic factor) [6], NT-3 (neurotrophin-3) and NGF (nerve growth factor) [7], cytokines such as CNTF (cilary neurotrophic factor) [8], HGF (hepatocyte growth factor) [9] and GDNF (glial-derived neurotrophic factor) [10] or hormones such as IGF-I (insulin-like growth factor I) [11] (Table 1).

Table 1
Neurotrophic factors and their receptors on the cell surface of motoneurons

? indicates unknown receptor part. CLF, cytokine-like factor; CNTFRα, CNTF receptor α; GFR, GFNF family receptor; gp, glycoprotein; IGFR, IGF receptor; LIFR, LIF receptor; p75NTR, p75 neurotrophin receptor; Trk, tropomyosin receptor kinase.

Class Receptor on motoneurons Reference(s) 
Neurotrophins   
 BDNF p75NTR, Trk-B [6,7
 NT-3 p75NTR, Trk-C [7
 NT-4/5 p75NTR, Trk-B [7
CNTF/LIF (leukaemia inhibitory factor) family 
 CNTF CNTFRα, LIFRβ, gp130 [8,40,41
 LIF LIFRβ, gp130 [42,43
 CT-1 (cardiotrophin-1) ?, LIFRβ, gp130 [44
 CLC (CT-1-like cytokine) CLF, LIFRβ, gp130 [45
HGF/SF (scatter factor) c-Met [46
IGFs   
 IGF-I IGFR-1 [47,48
 IGF-II IGFR-1, mannose [47
  6-phosphate receptor  
GDNF and related factors   
 GDNF GFRα1, c-Ret [10
 Neurturin GFRα2, c-Ret [10
 Persephin GFRα4, c-Ret [49
 Artemin GFRα3, c-Ret [50
Class Receptor on motoneurons Reference(s) 
Neurotrophins   
 BDNF p75NTR, Trk-B [6,7
 NT-3 p75NTR, Trk-C [7
 NT-4/5 p75NTR, Trk-B [7
CNTF/LIF (leukaemia inhibitory factor) family 
 CNTF CNTFRα, LIFRβ, gp130 [8,40,41
 LIF LIFRβ, gp130 [42,43
 CT-1 (cardiotrophin-1) ?, LIFRβ, gp130 [44
 CLC (CT-1-like cytokine) CLF, LIFRβ, gp130 [45
HGF/SF (scatter factor) c-Met [46
IGFs   
 IGF-I IGFR-1 [47,48
 IGF-II IGFR-1, mannose [47
  6-phosphate receptor  
GDNF and related factors   
 GDNF GFRα1, c-Ret [10
 Neurturin GFRα2, c-Ret [10
 Persephin GFRα4, c-Ret [49
 Artemin GFRα3, c-Ret [50

B-Raf is important for neuronal survival

Neurotrophic factors act through binding and activation of tyrosine kinase receptors which are phosphorylated upon activation. The signal is then transduced from the activated receptors to cytoplasmic and finally nuclear transduced proteins. Several signalling pathways are known for neurons. Upon these, the PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B) and the Ras/Raf (Ras-activated factor)/MAPK (mitogen-activated protein kinase) [12] pathways are known to be important for survival and maintenance of many neuronal cell populations (Figure 1). Both signalling pathways can interact at the level of activated Ras [13], a protein that plays a key role in the activation of Raf kinases, and through at least the direct interaction of B-Raf and Akt. Additional Raf-dependent signal transducing pathways are through C-Raf/Bag1 (Bcl-2-associated athanogene) [14] and Rap-1/B-Raf/cAMP [15]. Another activation of an intracellular signalling cascade occurs upon activation of cytokine receptors such as the CNTF receptor complex, the activation of STAT3 (signal transducer and activator of transcription 3). It has been thought for years that the activation of STAT3 would be essential for the survival of embryonic motoneurons. Latest results have proved that STAT3 activation protects postnatal lesioned motoneurons from cell death, but it is not involved in the survival of neuronal cells themselves [16].

Two important intracellular signalling cascades, the PI3K/Akt and the Ras/Raf/MAPK signalling pathway, are important for the survival of motoneurons

Figure 1
Two important intracellular signalling cascades, the PI3K/Akt and the Ras/Raf/MAPK signalling pathway, are important for the survival of motoneurons

A central task for both pathways is the phosphorylation of Bad. Phosphorylated Bad then interacts with 14-3-3 proteins and is withdrawn from the interaction partner Bcl-2 or Bcl-XL. Bcl-2 and Bcl-XL are anti-apoptotic members of the Bcl-2 family, while Bad is a pro-apoptotic member and therefore counteracts on this level. The phosphorylation of Bad furthermore prevents the release of cytochrome c from the mitochondria and thereby activation of caspases through the apoptosome complex.

Figure 1
Two important intracellular signalling cascades, the PI3K/Akt and the Ras/Raf/MAPK signalling pathway, are important for the survival of motoneurons

A central task for both pathways is the phosphorylation of Bad. Phosphorylated Bad then interacts with 14-3-3 proteins and is withdrawn from the interaction partner Bcl-2 or Bcl-XL. Bcl-2 and Bcl-XL are anti-apoptotic members of the Bcl-2 family, while Bad is a pro-apoptotic member and therefore counteracts on this level. The phosphorylation of Bad furthermore prevents the release of cytochrome c from the mitochondria and thereby activation of caspases through the apoptosome complex.

One major key consequence of neurotrophic factor activation is the increased expression of intracellular proteins that protect against apoptotic cell death. Proteins of the IAP (inhibitor of apoptosis protein)/ITA (inhibitor of T-cell apoptosis) family have such a function, especially IAP-1, IAP-2, XIAP (X-linked IAP) and survivin [17]. Proteins of the IAP/ITA family block activation of procaspase 9, which is activated by cytochrome c and Apaf-1 (apoptotic protease-activating factor 1). Furthermore, they block the function of activated caspases 3, 6, 7 and 8 and thereby can inhibit the apoptosis machinery activated by these proteins [18].

The Raf family in mammalian cells comprises three known members: C-Raf (also called Raf-1), A-Raf and B-Raf [19,20]. B-Raf exists in differentially spliced isoforms in the cells. Cells of the central nervous system (neurons and glia as well) mainly express B-Raf and C-Raf and, to a far lesser extent only, express A-Raf [12]. The cytoplasmic concentration of B-Raf in neuronal cells of the brain appears higher than that of C-Raf. Furthermore, B-Raf seems to be the main activator in neurons. In favour of this idea is the increased concentration of B-Raf in hippocampal neurons after cerebral ischaemia [21]. Gene targeting of B-Raf as well as C-Raf in mice results in an embryonic lethal phenotype [22,23]. Analysis of sensory neuron and motoneuron survival in B-Raf- and C-Raf-knockout mice revealed that these cells are dependent on the presence of B-Raf for their survival in culture [12].

Besides their signal transducing activity activating the MAPKs, B-Raf and C-Raf interact with several proteins, which either modulate their function through binding or by targeting to specific cellular compartments. One interesting interaction partner that has been shown to have an effect on survival of at least PC12 (pheochromocytoma) cells is the cochaperone of the Hsp70 (heat-shock protein 70), Bag1 [24].

Bag1 is necessary for phosphorylation of Bad (Bcl-2/Bcl-XL-antagonist, causing cell death) and subcellular distribution of B-Raf and Akt

Bag family proteins contain an evolutionarily conserved domain (the ‘BAG’ domain) that allows them to bind and modulate the activity of Hsp70 family molecular chaperones [25,26]. Humans and mice contain six genes encoding Bag family proteins, termed Bag1 (Rap46), Bag2, Bag3 (Bis), Bag4 (Sodd), Bag5 and Bag6 (Scythe) [27]. Bag1, which was first identified by its interaction with the anti-apoptotic protein Bcl-2, has been shown to protect a variety of types of cells from apoptosis in vitro [28], and overexpression of Bag1 in neurons has been shown to reduce stroke injury [29].

The mechanisms explaining how Bag1 inhibits apoptosis are poorly understood, and the physiological role of this protein during development is undefined. In addition to associating with Bcl-2, the Bag1 protein acts as a scaffold protein that binds C-Raf and B-Raf at the surface of mitochondria [30,31]. In this context, C-Raf could act as an effector kinase that phosphorylates Bad. Other kinases, particularly Akt, have also been shown to be active as a specific kinase for Bad [32]. As a consequence, Bad dissociates from Bcl-XL and this mechanism appears to be essential for survival of neurons. However, mice in which Ser112, Ser136 and Ser155 of Bad have been mutated are viable, but show enhanced cell death after exposure to pro-apoptotic stimuli and also a reduced threshold for cytochrome c release, thus underlining the importance of this protein for cellular survival [33]. Nevertheless, developmental cell death does not fully comprise the B-Raf phenotype, due to a timely different expression pattern of the Bag1 isoforms [34]. Developmental cell death is much more restricted in comparison with mice in which the B-Raf kinase has been inactivated [12].

In addition to their role in apoptosis, Bag family proteins have been shown to be involved in other cellular functions. A longer isoform of Bag1 containing nuclear-targeting sequences associates with several steroid hormone receptors, regulating their transcriptional activity [35]. Both the shorter cytosolic Bag1 and the longer nuclear Bag1L proteins interact with Hsp70, functioning as co-chaperones [36,37]. In this regard, Hsp70 has been shown to play a cytoprotective role in vivo [38]. Nevertheless, the relative importance of Bag-1 as a co-chaperone for Hsp70 in regulating apoptosis in vivo is unknown.

Targeted gene ablation of Bag1 in mice reveals an embryonic lethal phenotype at approximately E12–E13 (embryonic day 12–13). Inactivation of the bag1 gene has important consequences for survival of defined cell types in developing mice. In particular, the survival of haemopoietic and neural stem cells is severely impaired. This massive cell death occurs in association with loss of Bad phosphorylation at Ser136 [31]. In contrast with this effect, MAPK activity and Akt kinase activation are not changed. Phosphorylation of the transcription factor FKHR (forkhead in rhabdosarcoma), a specific substrate of Akt kinase, appears normal, and ERK1/2 (extracellular-signal-regulated kinase 1/2) activation in cultured bag1−/− fibroblasts after IGF-I stimulation appears unaltered. Bag1 is present in a complex with both B-Raf and Akt [4], and the formation of this complex is impaired in the bag1−/− mice [31]. Therefore Bag-1 seems to play a role in the subcellular distribution of B-Raf and Akt kinases as bag1/ mice show reduced levels of Akt and B-Raf protein at mitochondria. In addition, consistent with the previous results showing an absolute requirement for B-Raf in controlling an NGF-mediated survival pathway that involves induction of IAP gene expression in neurons [12], these findings reveal that Bag1, by interaction with Akt and Raf kinases, is essential for survival of stem cells in the developing brain. Cultured neural stem cells undergo apoptosis at a stage when they express Pax6, a marker for neural precursor cells that is required to regulate the cell cycle and the rate of progression from symmetrical to asymmetrical division [39], and thus represents an important physiological mediator of extracellular survival signals that prevent apoptosis.

International Symposium on Neurodegeneration and Neuroprotection: Independent Meeting held at University of Münster, Germany, 23–27 July 2006. Organized and Edited by S. Klumpp and J. Krieglstein (Münster, Germany).

Abbreviations

     
  • Bad

    Bcl-2/Bcl-XL-antagonist, causing cell death

  •  
  • Bag1

    Bcl-2-associated athanogene 1

  •  
  • BDNF

    brain-derived neurotrophic factor

  •  
  • CNTF

    ciliary neurotrophic factor

  •  
  • GDNF

    glial-derived neurotrophic factor

  •  
  • HGF

    hepatocyte growth factor

  •  
  • Hsp70

    heat-shock protein 70

  •  
  • IAP

    inhibitor of apoptosis protein

  •  
  • IGF

    insulin-like growth factor

  •  
  • ITA

    inhibitor of T-cell apoptosis

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • NT-3

    neurotrophin-3

  •  
  • NGF

    nerve growth factor

  •  
  • PI3K

    phosphoinositide 3-kinase

  •  
  • Raf

    Ras-activated factor, STAT, signal transducer and activator of transcription

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