Regenerating Islet-derived 1a (Reg-1a) Proteinis a new neuronal secreted factor that stimulates neurite outgrowth via the Exostosin tumor-like 3 (EXTL3) receptor.

Regenerating islet-derived1a(Reg-1a) /lithostathine, a member of a family of secreted proteins containing a C-type lectin domain, is expressed in various organs and plays a role in proliferation, differentiation, inflammation and carcinogenesis of cells of the digestive system. We previously reported that Reg-1α is over-expressed during the very early stages of Alzheimer disease and Reg-1α deposits were detected in the brain of patients with Alzheimer disease. However, the physiological function of Reg-1α in neural cells remains unknown. Here, we show that Reg-1α is expressed in neuronal cell lines (PC12 and Neuro-2a) and in rat primary hippocampal neurons (E17.5). Reg-1α is mainly localized around the nucleus and at the membrane of cell bodies and neurites. Transient over-expression of Reg-1α or addition of recombinant Reg-1α significantly increases the number of cells with longer neurites by stimulating neurite outgrowth. These effects are abolished upon down-regulation of Reg-1α by siRNA and following inhibition of secreted Reg-1α by antibodies. Moreover, Reg-1α colocalizes with Exostosin tumor- like 3 (EXTL3), its putative receptor, at the membrane of these cells. Over-expression of EXTL3 increases the effect of recombinant Reg-1α on neurite outgrowth, and Reg-1α is not effective when EXTL3 over-expression is down-regulated by shRNA. Our findings indicate that Reg-1α regulates neurite outgrowth and suggest that this effect is mediated by its receptor EXTL3