This project by studying the role of Shh in a variety of contexts will allow us to determine 1) the temporal requirement for hedgehog signaling within the telencephalon, 2) the genetic interactions between Shh, Gli3 and Pax6, which cumulatively appear to be the central interactions underlying Shh function during telencephalic patterning 3) the requirement for Shh in maintaining the specific sub-lineages in the SVZ stem cell niche and 4) the question of which specific Gli genes are required for later Shh-mediated support of these same postnatal SVZ progenitors. Sonic Hedgehog (Shh) signaling is central in the establishment of dorsoventral pattern within the telencephalon. Specifically, gain and loss of function analyses of Shh signaling in the telencephalon have suggested that this diffusible signaling molecule is essential for the expression or repression of characteristic transcription factors which specify ventral or dorsal identities, respectively. With regard to regional specification within the telencephalon, the actions of Shh in patterning the dorsal midline are particularly poorly understood. In addition, we recently have shown that Shh acts in maintaining stem cells within the postnatal telencephalon. In this grant we will take a genetic approach to determine the specific cell lineages that require Shh signaling. First, we propose to study temporal requirement for Shh-signaling between E9.0 and E12.5, the time period during which dorsoventral patterning within the telencephalon is established. To further our understanding of Shh's role in this process we propose a three-way loss of function analysis of Shh, Gli3 and Pax6. In the second portion of the grant we will examine which lineages in the peri- and postnatal SVZ stem ceil niche require hedgehog signaling. We will accomplish this by temporal and cell specific deletion of both Shh and the obligate hedgehog effector gene Smo, using lineage specific inducible Cre driver lines. Finally, we propose to use knock out (Gli1) and conditional null alleles (Gli2 and Gli3) of the three Gli genes to examine their requirement in these later processes. Together this proposal will provide a comprehensive examination of Shh signaling during telencephalic development.
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