Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
International Research Center for Neurointelligence (WPI-IRCN), The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Sci Rep. 2021 Jan 12;11(1):613. doi: 10.1038/s41598-020-79610-6.
The lateral ventricles of the adult mammalian brain are lined by a single layer of multiciliated ependymal cells, which generate a flow of cerebrospinal fluid through directional beating of their cilia as well as regulate neurogenesis through interaction with adult neural stem cells. Ependymal cells are derived from a subset of embryonic neural stem-progenitor cells (NPCs, also known as radial glial cells) that becomes postmitotic during the late embryonic stage of development. Members of the Geminin family of transcriptional regulators including GemC1 and Mcidas play key roles in the differentiation of ependymal cells, but it remains largely unclear what extracellular signals regulate these factors and ependymal differentiation during embryonic and early-postnatal development. We now show that the levels of Smad1/5/8 phosphorylation and Id1/4 protein expression-both of which are downstream events of bone morphogenetic protein (BMP) signaling-decline in cells of the ventricular-subventricular zone in the mouse lateral ganglionic eminence in association with ependymal differentiation. Exposure of postnatal NPC cultures to BMP ligands or to a BMP receptor inhibitor suppressed and promoted the emergence of multiciliated ependymal cells, respectively. Moreover, treatment of embryonic NPC cultures with BMP ligands reduced the expression level of the ependymal marker Foxj1 and suppressed the emergence of ependymal-like cells. Finally, BMP ligands reduced the expression levels of Gemc1 and Mcidas in postnatal NPC cultures, whereas the BMP receptor inhibitor increased them. Our results thus implicate BMP signaling in suppression of ependymal differentiation from NPCs through regulation of Gemc1 and Mcidas expression during embryonic and early-postnatal stages of mouse telencephalic development.
成年哺乳动物大脑的侧脑室由单层纤毛室管膜细胞组成，这些细胞通过纤毛的定向摆动产生脑脊液流动，并通过与成年神经干细胞的相互作用调节神经发生。室管膜细胞来源于一组胚胎神经干细胞-祖细胞（NPCs，也称为放射状胶质细胞），这些细胞在胚胎发育的晚期进入有丝分裂后期。转录调节因子 Geminin 家族的成员，包括 GemC1 和 Mcidas，在室管膜细胞的分化中发挥关键作用，但仍不清楚哪些细胞外信号在胚胎和出生后早期发育过程中调节这些因子和室管膜细胞分化。我们现在表明，在与室管膜分化相关的小鼠外侧神经节隆起的脑室-室下区细胞中，Smad1/5/8 磷酸化和 Id1/4 蛋白表达的水平下降，而 Smad1/5/8 磷酸化和 Id1/4 蛋白表达都是骨形态发生蛋白（BMP）信号的下游事件。将出生后 NPC 培养物暴露于 BMP 配体或 BMP 受体抑制剂中，分别抑制和促进多纤毛室管膜细胞的出现。此外，BMP 配体处理胚胎 NPC 培养物降低了室管膜标记物 Foxj1 的表达水平，并抑制了室管膜样细胞的出现。最后，BMP 配体降低了出生后 NPC 培养物中 Gemc1 和 Mcidas 的表达水平，而 BMP 受体抑制剂则增加了它们的表达水平。我们的研究结果表明，BMP 信号通过调节胚胎和出生后早期小鼠端脑发育过程中 Gemc1 和 Mcidas 的表达，抑制 NPC 向室管膜细胞分化。
