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リエゾンラボ研究会
発表内容

Title:
A Matter of Commitment: a Possible Role of TGFß/BMP Signaling in the Regulation of Neural Stem/Progenitor Cells in the Postnatal Mouse Brain

Yasuhide Furuta
Laboratory for Animal Resources & Genetic Engineering (LARGE), RIKEN Center for Developmental Biology (CDB), Kobe ; Laboratory Head

Abstract:
Recent studies have suggested that transforming growth factor-ß (TGFß) super-family signaling, consisting of canonical TGFß/activin- and bone morphogenetic protein (BMP) branch pathways, are involved in the regulation of adult neurogenesis. It has also been suggested that TGFß/BMP signaling can be a potential therapeutic target for brain tumors. However, still little is known about molecular mechanisms by which the TGFß signaling system regulates adult neurogenesis. We have examined the role of Smad4, a key integrator of TGFß/BMP signaling pathways, in the regulation of neural progenitor cells in the subventricular zone (SVZ), one of the major sites of neurogenesis in the postnatal mouse brain. We have obtained a body of evidence that neural progenitor cells that lack the function of Smad4 fail to commit to a neuronal fate and to maintain neural stem-like characteristics in vivo and in vitro. More recently, we found that combined loss of Samd4 and a tumor suppressor gene P53 leads to tumorous lesions in the mutant mouse brain. These results strongly suggest that Smad4 plays an important role within the nascent neural progenitor cell population during establishment of a committed progenitor state and subsequent neuronal differentiation in the postnatal mouse brain. Further we hypothesize that sustained stem cell-like characteristics in TGFß signaling-deficient neural progenitor cells can predispose them to an accumulation of oncogenic mutations, thereby increasing susceptibility to brain tumors. Future studies will be aimed at identification of Smad4 downstream target genes to facilitate the understanding of molecular function of TGFß signaling in adult neural stem/progenitor cells and brain tumor initiating cells.