Mechanisms Regulating Astroglial Lineage Development

EXCEED THE SPACE PROVIDED. During mammalian cerebral cortical development, neural stem cells (NSCs) give rise to successive waves of neurons and glia. We have shown that the bone morphogenetic proteins (BMPs) promote specific lineage decisions that depend on the developmental stage of NSCs. Within the early embryonic ventricular zone (VZ), BMPs initially enhance cell death but later promote neuronal lineage commitment and subsequent cellular maturation and also actively suppress the generation of radial glia and oligodendrocytes. By contrast, within the late embryonic subventricular zone (SVZ), BMPs potentiatethe elaborationof astrocytesand nowactively suppress the elaboration of neurons and also oligodendrocytes. Members of the inhibitor of differentiation(ID) family regulate neurogenic basic-helix-loop-helix (bHLH) transcription factors, and ID1 and 3 inhibit neurogenesis while simultaneously preserving the NSC fate. We have found that during both embryonic neurogenesis and gliogenesis, BMPs upregulate transcripts for ID2 and ID4 in NSCs and promote ID nuclear translocation in target progenitor species. We hypothesizethat BMP-mediated cellular and lineage effects involve ID2and ID4 because inhibition of ID2 and/or ID4 expression prevents these BMP-sanctioned positive and negative developmental effects on VZ and SVZ NSCs, and preliminary analysis of ID2-/-, ID4-/- and ID2-/-ID4-/- mice has revealed defects in neural development distinct from those seen with ID1-/-, ID3-/- and ID1-/-ID3-/-mice. The basic hypotheses underlying this proposal are: 1. BMPs orchestrate cortical developmental events by promotion of specific pathways of NSC differentiation as well as active suppression of alternate lineage fates, 2. BMPs also modulate the size of the initial VZ NSC pool and progressive stages of neuronal maturation, 3. ID2 and ID4 differentially mediate these diverse processes through changing roles within distinct progenitor species.The role of ID2 and ID4 in cortical development will be examined in vitro by defining the effects of overexpressingor ablating ID2 and/or ID4 on NSC lineage commitment and responses to the BMPs. Their roles will be examined in vivo by analyzing neural development in ID2-/-, ID4-/- and ID2-/-ID4-/-mutant mice. These studies will further our understandingof the molecular mechanisms governing the changing profiles of neural lineage elaboration during embryonic cerebralcortical neurogenesis and gliogenesis.