UCSF

To understand how the complex architecture of the brain is formed during

development, it is essential to identify the signals that regulate the behaviors of neural progenitor cells. To date, many of the signals that regulate cell proliferation and differentiation of neuronal and glial progenitors of the neocortex are unknown. For my primary thesis work, I investigated the role of the Wnt-β-catenin intercellular signaling pathway in the behaviors of neural progenitors of the mouse neocortex. In this study, we show that the Wnt-β-catenin pathway (WBP) regulates the differentiation of intermediate progenitors (IPs; also known as basal progenitors) into neurons. Upregulation of the WBP by overexpression of Wnt3a secreted agonist in the neocortex induced early differentiation of IPs into neurons and the accumulation of these newly born neurons at the border of the subventricular zone and intermediate zone. Long-term overexpression of Wnt3a led to cortical dysplasia associated with the formation of large neuronal heterotopias. Conversely, downregulation of the WBP with Dkk1, a secreted Wnt antagonist, during mid and late stages of neurogenesis inhibited neuronal production. Lastly, consistent with previous reports, we also show that the WBP also promotes radial glia (RG) expansion. Thus, our findings show differential effects of the WBP on distinct groups of cortical neuronal progenitors: RG expansion and IP differentiation. Moreover, these findings suggest that dysregulation of the WBP can lead to developmental defects similar to human cortical malformation disorders. In a collaborative project, I contributed to address the role of the WBP in oligodendrogenesis. The WBP has previously been shown to inhibit the maturation of oligodendrocyte precursor cells (OPCs). Here, we show that the WBP also inhibits the production of OPCs using both in vitro and in vivo approaches. Our in vivo results show that downregulation of the WBP with a dominant negative form of LEF1 transcription factor or Dkk1 promoted early production of OPCs in the neocortex. Together with previous work, these findings identify multiple roles for the WBP in both neurogenesis and oligodendrogenesis.