Sonic hedgehog (Shh) signaling is involved in various developmental processes that include patterning, cell specification and proliferation. Mutations in Shh signaling pathway have been associated with numerous diseases in human including cancer. Recently, Shh signaling has been also implicated in promoting proliferation of neural stem cells (NSC) in the forebrain. Using the genetic fate mapping approach in mice, we have discovered that adult NSCs in forebrain respond to Shh signaling, self-renew, and generate multiple cell types of the nervous system. These results provided the first in vivo evidence that there exists an endogenous cell population that meets all the criteria of the NSCs. We are interested in elucidating the mechanism by which Shh signaling maintains and regulates proliferation and differentiation of the quiescent NSCs during normal and pathological conditions in adult mouse. Moreover, discovery of novel downstream target genes of Shh-signaling in NSCs will provide further understanding of stem cell behavior. Finally, we will investigate the biological role of the newly generated neurons in the adult mouse forebrain by analysing the neural circuits formed by these newborn neurons. These studies will provide the necessary foundation for stem cell biology to develop therapeutic methods in treating various neurodegenerative diseases.? ? The molecular mechanism by which Shh acts on neural stem cells? Ahn, Cheney? The Gli2 (activator) and Gli3 (repressor) transcription factors are the major effectors of Shh signaling. In developing neural tube, the dorso-ventral patterning is mediated by Shh-induced activation of Gli2 transcription factor whereas the anterior-posterior patterning of developing limb is mediated through the inhibition of Gli3 repressor (Gli3R) by Shh activity. It is thus possible that proliferation of Shh-responding neural stem cells depend on relative levels of Gli2 and Gli3R. We have begun analyzing the requirement for Gli2/3 by determining the fate of adult neural stem cells (Gli1-CreER-derived cells) in Gli2 and Gli3 mutant backgrounds by using conditional mutant alleles of Gli2 and Gli3 mice (generated in the Joyner lab). In addition to Gli1-CreER mice, we are also using nestin-Cre mice to delete Gli2 or Gli3 from all the neuronal progenitors to investigate the developmental requirements of Gli2 or Gli3 specifically in neuronal populations. ?
