Sonic hedgehog (Shh) is a secreted protein that plays diverse roles in developing embryos and has been also implicated in the ongoing neurogenesis in the postnatal forebrain. She utilized an in vivo genetic fate mapping strategy using Gli1 as a sensitive read-out of Shh activity to systematically mark and follow the fate of Shh-responding cells in mouse (Ahn and Joyner 2004 Cell; Ahn and Joyner 2005 Nature). She demonstrated that only a small initial population of cells that include both quiescent neural stem cells (NSCs) and transit-amplifying (TA) cells responds to Shh in the neurogenic regions, but subsequently expands dramatically to continuously provide new neurons in the forebrain. Her study of the behavior of quiescent NSCs provides the first in vivo evidence that they can self-renew for over a year and generate multiple cell types (Ahn and Joyner 2005 Nature). Based on these results, Dr. Ahn's Unit on Developmental Neurogenetics will continue to investigate the biology of adult neural stem cells: First, the mechanism by which Shh maintains or promotes the survival/proliferation of NSCs: Second, the identity of genes that are specifically expressed in the quiescent NSCs vs. proliferating TA cells: Third, the function of newly generated neurons in the hippocampus in neural circuit formation and plasticity. Combining the sophisticated mouse genetics approaches with molecular and cellular biology techniques in her Unit will provide insights into the cellular and genetic mechanisms underpinning neural stem cell specification and lineage decisions.
Figure 1. Using the Genetic Inducible Fate mapping technique based on the inducible Cre recombinase/loxP system, Shh- responding (Gli1-expressing) neural stem cells are permanently marked in Gli1-CreER; Tau-stop-mGFP-IRES-nlacZ mice following Tamoxifen administration. New granule neurons generated from these stem cells in the adult dentate gyrus of the hippocampus can be visualized by their nuclear lacZ (Red) expression and projections (Green) toward CA3 region. (Blue: DAPI nuclear counter-staining).
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