Asymmetric EGFR distribution during neural development and the default cell fate of neural stem cells

The development of central nervous system (CNS) can be simplified as a process whereby neural stem/progenitor cells acquire developmental information and produce diverse neural progeny in a precisely temporal and regional order. Based on EGFR immunostaining, we have found that in mouse embryonic forebrain ventricular and subventricular zones, the EGFR shows asymmetric distribution during mitosis in vivo and in vitro. This phenomenon is further confirmed with two additional approaches: EGFR labeling with fluorescence-conjugated EGFR ligand and live tracing of EGFR distribution with ectopically expressed human EGFReGFP fusion construct. EGFR asymmetric distribution occurs during divisions yielding two Nestin+ progenitor cells, via an actin-dependent mechanism. The resulting sibling progenitor cells reveal divergence in cell fates with different response to EGFR ligand in terms of migration and proliferation, and radial glial/astrocytic marker expressions. A combination of different neural progenitor cell markers applied to lineage trees of cultured cortical glioblasts, further reveals an asymmetric division pattern underlying gliogenesis.; Opposite to investigating the effects of extrinsic signals on the diversification of neural stem/progenitor cells, we have explored the default state of neural stem cells---a cell fate acquired in the absence of growth factors. By using clonal analysis, we have found that, regardless of developmental stages, neural stem cells differentiate into neurons when cultured in a defined serum-free and no exogenous growth factor containing medium. With the retained regional information, most neural stem cells from cortical region differentiate into glutamatergic pyramidal neurons in the default condition, whereas those from basal forebrain take GABAergic neuronal subtypes. Furthermore, this neuronal differentiation by elimination of extrinsic growth factors can be recreated in an ex vivo model---adult SVZ whole mount organotypic culture.; Taken together, our data indicate that cell surface receptors can be directly involved in neural cell diversification via asymmetric distribution during mitosis and creating two sibling cells with different responses to environmental cues; secondly, in spite of the heterogeneity of neural stem cells, neuronal differentiation is a common feature when extrinsic growth factors are eliminated. The interplay between intrinsic programs and extrinsic signals in stem and progenitor cells is an essential process underlying CNS development.