CONSERVATION OF THE NOTCH SIGNALING PATHWAY IN MAMMALIAN NEUROGENESIS

The Notch pathway functions in multiple cell fate determination proces ses in invertebrate embryos, including the decision between the neurob last and epidermoblast lineages in Drosophila, In the mouse, targeted mutation of the Notch pathway genes Notch1 and RBP-Jk has demonstrated a role for these genes in somite segmentation, but a function in neur ogenesis and in cell fate decisions has not been shown. Here we show t hat these mutations lead to altered expression of the Notch signalling pathway homologues Hes-5, Mash-1 and Dll1, resulting in enhanced neur ogenesis, Precocious neuronal differentiation is indicated by the expa nded expression domains of Math4A, neuroD and NSCL-1. The RBP-Jk mutat ion has stronger effects on expression of these genes than does the No tch1 mutation, consistent with functional redundancy of Notch genes in neurogenesis. Our results demonstrate conservation of the Notch pathw ay and its regulatory mechanisms from fly to mouse, and support a role for the murine Notch signalling pathway in the regulation of neural s tem cell differentiation.