Distinct human NUMB isoforms regulate differentiation vs. proliferation inthe neuronal lineage

Neuronal cell fate decisions are directed in Drosophila by NUMB, a signalin g adapter protein with two protein-protein interaction domains: a phosphoty rosine-binding domain and a proline-rich region (PRR) that functions as an SH3-binding domain, Here we show that there are at least four human NUMB is oforms and that these serve two distinct developmental functions in the neu ronal lineage: differentiation (but not proliferation) is promoted by human NUMB protein isoforms with a type I (short) PRR. In contrast, proliferatio n (but not differentiation) is directed by isoforms that have a type II (lo ng) PRR, The two types of PRR may promote distinct intracellular signaling pathways downstream of the NOTCH receptor during mammalian neurogenesis.