Sonic hedgehog (Shh) promotes proliferation of neural stem cells (NSCs) in adult brain. However, Shh signaling does not act on NSCs until late gestational stages, suggesting that embryonic NSCs (= radial glia cell) and postnatal NSCs are differentially regulated for their proliferation. Furthermore, postnatal neurogenic niche contains various cell types such as ependymal cells that are also derived from embryonic NSCs around birth. Yet, how the distinct niche cell types are specified remains unclear. We focused on the Gli family of transcription factors (Gli1, Gli2, Gli3), which are activated or modified in response to Shh activity to better understand the molecular regulatory mechanism of Shh signaling. In particular, Gli3 is processed into a repressor form (Gli3R) in the absence of Shh signal and acts as the major negative transducer of the pathway. We have investigated the role of Gli3 as a repressor in two systems in which Shh activity is lacking: the developing dorsal forebrain and the embryonic NSCs. Our findings demonstrate the novel role of Gli3R in regulation of neural stem/progenitors in developing brain and in postnatal neurogenic niche. The role of Gli3 in establishment of postnatal neurogenic niche: Right around the birth, embryonic radial glia give rise to postnatal NSCs and ependymal cells to constitute the neurogenic niche in the subventricular zone of the lateral ventricle in the mouse forebrain. Since Shh positive signaling begins around this transition, we addressed the role of Gli3 repressor in the absence of Shh signaling in shaping this postnatal neurogenic niche. Our conditional genetic deletion approaches demonstrated that Gli3 repressor is critical in specification of postnatal ependymal cells and NSCs. First, Gli3 repressor is required to suppress gp130/STAT3 signaling at the transcriptional level to regulate the amount of GFAP-expressing glia cells in the SVZ. Next, Gli3 repressor is required to maintain the appropriate amount of Numb protein via LNX ubiquitin ligase. The loss of Numb led to the disruption in cell adhesion between ependymal cels and NSCs, resulting in compromised neurogenic activity of neighboring NSCs. Taken together, we provide a novel mechanism of the establishment of the SVZ niche structure and neurogenesis through the interplay between NSCs and environment. Gene expression profiling of adult neural stem cells and their niche: The neurogenic niche contains several distinct types of cells and interacts with the NSCs in the subventricular zone (SVZ) of the lateral ventricle. While several molecules produced by the niche cells have been identified to regulate adult neurogenesis, a systematic profiling of autocrine/paracrine signaling molecules in the neurogenic regions involved in maintenance, self-renewal, proliferation, and differentiation of NSCs has not been done. We took advantage of the genetic inducible fate mapping system (GIFM) and transgenic mice to isolate the SVZ niche cells including NSCs, transit-amplifying progenitors (TAPs), astrocytes, ependymal cells, and vascular endothelial cells. From the isolated cells and microdissected choroid plexus, we obtained the secretory molecule expression profiling (SMEP) of each cell type using the Signal Sequence Trap method. We identified a total of 151 genes encoding secretory or membrane proteins. In addition, we obtained the potential SMEP of NSCs using cDNA microarray technology. Through the combination of multiple screening approaches, we identified a number of candidate genes with a potential relevance for regulating the NSC behaviors, which provide new insight into the nature of neurogenic niche signals.

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Lee, Cheol; Hu, Jingqiong; Ralls, Sherry et al. (2012) The molecular profiles of neural stem cell niche in the adult subventricular zone. PLoS One 7:e50501
Wang, Hui; Ge, Guannan; Uchida, Yutaka et al. (2011) Gli3 is required for maintenance and fate specification of cortical progenitors. J Neurosci 31:6440-8
Hayes, Lindsay; Zhang, Zhiwei; Albert, Paul et al. (2011) Timing of Sonic hedgehog and Gli1 expression segregates midbrain dopamine neurons. J Comp Neurol 519:3001-18
Bouldin, Cortney M; Gritli-Linde, Amel; Ahn, Sohyun et al. (2010) Shh pathway activation is present and required within the vertebrate limb bud apical ectodermal ridge for normal autopod patterning. Proc Natl Acad Sci U S A 107:5489-94
Carney, Rosalind S E; Mangin, Jean-Marie; Hayes, Lindsay et al. (2010) Sonic hedgehog expressing and responding cells generate neuronal diversity in the medial amygdala. Neural Dev 5:14