Mammalian Numb (mNumb) has multiple functions and plays important roles in the regulation of neural development, including maintenance of neural progenitor cells and promotion of neuronal differentiation in the central nervous system (CNS). However, the molecular bases underlying the distinct functions of Numb have not yet been elucidated. mNumb, which has four splicing isoforms, can be divided into two types based on the presence or absence of an amino acid insert in the proline-rich region (PRR) in the C-terminus. It has been proposed that the distinct functions of mNumb may be attributable to these two different types of isoforms. In this study, we used the outer optic anlage (OOA) of the Drosophila larval brain as an assay system to analyze the functions of these two types of isoforms in the neural stem cells, since the proliferation pattern of neuroepithelial (NE) stem cells in the OOA closely resembles that of the vertebrate neural stem/progenitor cells. They divide to expand the progenitor cell pool during early neurogenesis and to produce neural precursors/neurons during late neurogenesis. Clonal analysis in the OOA allows one to discriminate between the NE stem cells, which divide symmetrically to expand the progenitor pool, and the postembryonic neuroblasts (pNBs), which divide asymmetrically to produce neural precursors (ganglion mother cells), each of which divides once to produce two neurons. We found that in the OOA, the human Numb isoform with a long PRR domain (hNumb-PRRL), which is mainly expressed during early neurogenesis in the mouse CNS, promotes proliferation of both NE cells and pNBs without affecting neuronal differentiation, while the other type of hNumb isoform with a short PRR domain (hNumb-PRRS), which is expressed throughout neurogenesis in the mouse embryonic CNS, inhibits proliferation of the stem cells and promotes neuronal differentiation. We also found that hNumb-PRRS, a functional homologue of Drosophila Numb, more strongly decreases the amount of nuclear Notch than hNumb-PRRL, and could antagonize Notch functions probably through endocytic degradation, suggesting that the two distinct types of hNumb isoforms could contribute to different phases of neurogenesis in the mouse embryonic CNS.
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