Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan; Department of Biochemistry and Molecular Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan.
Mol Cell Neurosci. 2017 Sep;83:55-64. doi: 10.1016/j.mcn.2017.06.008. Epub 2017 Jun 29.
Signaling by the TGFβ super-family, consisting of TGFβ/activin- and bone morphogenetic protein (BMP) branch pathways, is involved in the central nervous system patterning, growth, and differentiation during embryogenesis. Neural progenitor cells are implicated in various pathological conditions, such as brain injury, infarction, Parkinson's disease and Alzheimer's disease. However, the roles of TGFβ/BMP signaling in the postnatal neural progenitor cells in the brain are still poorly understood. We examined the functional contribution of Smad4, a key integrator of TGFβ/BMP signaling pathways, to the regulation of neural progenitor cells in the subventricular zone (SVZ). Conditional loss of Smad4 in neural progenitor cells caused an increase in the number of neural stem like cells in the SVZ. Smad4 conditional mutants also exhibited attenuation in neuronal lineage differentiation in the adult brain that led to a deficit in olfactory bulb neurons as well as to a reduction of brain parenchymal volume. SVZ-derived neural stem/progenitor cells from the Smad4 mutant brains yielded increased growth of neurospheres, elevated self-renewal capacity and resistance to differentiation. These results indicate that loss of Smad4 in neural progenitor cells causes defects in progression of neural progenitor cell commitment within the SVZ and subsequent neuronal differentiation in the postnatal mouse brain.
TGFβ 超家族信号通路，包括 TGFβ/激活素和骨形态发生蛋白 (BMP) 分支途径，参与胚胎发生过程中中枢神经系统的模式形成、生长和分化。神经祖细胞与各种病理状况有关，如脑损伤、梗死、帕金森病和阿尔茨海默病。然而，TGFβ/BMP 信号通路在出生后大脑神经祖细胞中的作用仍知之甚少。我们研究了 Smad4（TGFβ/BMP 信号通路的关键整合因子）对侧脑室下区 (SVZ) 神经祖细胞调节的功能贡献。神经祖细胞中 Smad4 的条件缺失导致 SVZ 中类似神经干细胞的数量增加。成年大脑中的 Smad4 条件性突变体也表现出神经元谱系分化的减弱，导致嗅球神经元减少以及脑实质体积减少。来自 Smad4 突变体大脑的 SVZ 源性神经干细胞/祖细胞导致神经球生长增加、自我更新能力增强和分化抵抗。这些结果表明，神经祖细胞中 Smad4 的缺失导致 SVZ 中神经祖细胞的进展出现缺陷，随后在出生后小鼠大脑中出现神经元分化缺陷。
