Intracellular sortilin expression pattern regulates proNGF-induced naturally occurring cell death during development

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Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) can support the survival and differentiation of neural cells during development and regeneration. The control of cell survival by neurotrophins is mediated by two types of transmembrane glycoprotein, the trk tyrosine kinase (Trk) receptors and the neurotrophin receptor p75 (p75^NTR). Neurotrophins affect neural cell survival by activating Trk receptors, whereas NGF binding to p75^NTR can activate an intracellular pathway similar to that activated by death receptors.¹ We previously documented that p75^NTR is expressed in postmitotic mouse retinal ganglion cells (RGCs) and induces programmed cell death before embryonic day (E) 15.² This function may contribute to the appropriate RGC number control and optic nerve formation. However, despite its stable expression, p75^NTR-dependent RGC death is inhibited after E17 by as yet unknown mechanisms. Recent studies have shown that the unprocessed precursor form of neurotrophin family members (pro-neurotrophins), such as proNGF and proBDNF, can act through a co-receptor system of p75^NTR and sortilin to mediate cell apoptosis.^{3, 4, 5} Although the expression and function of sortilin in vivo remain unclarified, it might be involved in the programmed RGC death that is observed only in the early phase of retinal development. Thus, we were interested in the expression and functions of p75^NTR/sortilin receptor complex in the developing retina.

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