Prolactin receptor heterogeneity: processing and signalling of the long and short isoforms during development

During development, the fetus is exposed to prolactin activity from the placenta, as well as from the developing fetal pituitary. Distinct prolactin receptor isoforms, having different cytoplasmic domains generated by alternative splicing, are expressed as development proceeds at different levels in different organs. The ‘long’ receptors are able to mediate transduction of all signals examined, in contrast with the ‘short’ isoforms, whose truncated cytoplasmic domains are able to mediate a much smaller repertoire of signals and can act as dominant negatives. Our studies demonstrate that, although these forms share internalization mechanisms, the long form is internalized faster, resulting in more rapid down-regulation of this form. In order to examine the mechanisms by which prolactin may exert trophic effects on its target tissues during development, we have examined the signalling pathways through which prolactin binding to the long receptor regulates the transcription of cyclin D1. Our studies reveal the importance of the JAK/STAT (Janus kinase/signal transduction and activators of transcription) pathway, and the complexity of prolactin signalling to this promoter.