The overall goal is to understand the mechanisms by which immature cells in the developing CMSare specified to particular fates. We have focused on the subventricular zone (SVZ) of the neonatal forebrain in rodents. Immature cells in this area give rise contemporaneously to neurons (olfactory interneurons) and glia (both astrocytes and oligodendrocytes). We are able in this system to combine in vivo (retroviral gene transfer) with in vitro (cell isolations and culture) studies. Thus, this region of the developing CMS is a particularly attractive one for studying early fate specification. We will pursue several questions. 1. Are the transcription factors olig2 and Pax6 important for a neuronal-glial fate decision in SVZ cells? We will explore the hypotheses that olig genes specify a pan-glial lineage in the neonatal SVZ. Does olig2 repress neuronal genes? Is there a reciprocal relationship between olig2 and Pax6 expression? Does Pax6 expression influence olig expression, and if so, in what way? To determine if glia are the only descendants of olig2+ SVZ cells, or if neurons also arise from olig2+ cells, we will use the olig2-cre knock-in mouse for long-term lineage tracing. 2. Does olig2 play a role in glial progenitor specification into astrocyte and oligodendrocyte lineages? Specifically, does astrocyte differentiation require the downregulation of olig2? Doesastrocyte development require the eventual loss of olig2 from olig+ cells? Is the downregulation of oligs produced by members of the BMP and IL-6 families? We will explore the hypothesis that olig-expressing glial progenitors must downregulate oligs to differentiate fully into astrocytes. We will isolate glial (olig2+) progenitors from the SVZ of the olig2-eGFP mouse and examine in vitro how the exposure to BMPs (BMP2, 4) and IL-6 (LIF and CNTF) proteins influences an astrocyte-oligodendrocyte fate decision. Is the expression of Id proteins altered during astrocyte development, and how might Id proteins contribute to astrocyte development? Loss of olig function may be produced by members of the BMP and IL-6 families via induction of member(s) of the Id family. We will ask if Ids are up- or down-regulated by exposure of olig2+ cells to BMPs. We will also ask if Id expression is a necessary step in the BMP induction of an astrocyte fate in olig+ cells. We will examine these issues in vitro and in vivo.
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