Wnt/β-Catenin Signaling Regulates Sequential Fate Decisions of Murine Cortical Precursor Cells
Wnt/β-Catenin Signaling Regulates Sequential Fate Decisions of Murine Cortical Precursor Cells
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DOI：
10.1002/stem.1820
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发表时间：
2015-01-01
期刊：
影响因子：
5.2
通讯作者：
Sommer, Lukas
中科院分区：
文献类型：
--
作者：
Draganova, Kalina;Zemke, Martina;Sommer, Lukas
神经前体细胞(NPC)的命运由内在程序和外在信号的复杂相互作用决定，其中很少有人知道。β-连环蛋白转导细胞外的Wnt信号，但也维持附着连接的完整性。在这里，我们通过将一种新的β-连环蛋白突变等位基因与条件性失活方法相结合，首次确定了β-连环蛋白转录活性的贡献，而不是其在大脑皮层发育中的黏附作用。WNT/β-catenin信号消融导致鼻咽癌过早分化，但除此之外，还会改变祖细胞周期动力学，增加基本分裂的祖细胞。有趣的是，Wnt/β-catenin信号影响前体细胞的顺序命运转换，导致神经发生周期缩短，深层和上层神经元数量减少，随后导致早熟星形形成。事实上，一项全基因组分析强调了Wnt/β-catenin信号消融的皮质中皮质生成分化程序的过早激活。因此，β-连环蛋白信号控制一组基因的表达，这些基因似乎作用于典型的Wnt信号的下游，以调节前脑中适当的祖细胞数量、神经元亚群和星形胶质细胞的特定阶段的产生。
The fate of neural progenitor cells (NPCs) is determined by a complex interplay of intrinsic programs and extrinsic signals, very few of which are known. beta-Catenin transduces extracellular Wnt signals, but also maintains adherens junctions integrity. Here, we identify for the first time the contribution of beta-catenin transcriptional activity as opposed to its adhesion role in the development of the cerebral cortex by combining a novel beta-catenin mutant allele with conditional inactivation approaches. Wnt/beta-catenin signaling ablation leads to premature NPC differentiation, but, in addition, to a change in progenitor cell cycle kinetics and an increase in basally dividing progenitors. Interestingly, Wnt/beta-catenin signaling affects the sequential fate switch of progenitors, leading to a shortened neurogenic period with decreased number of both deep and upper-layer neurons and later, to precocious astrogenesis. Indeed, a genome-wide analysis highlighted the premature activation of a corticogenesis differentiation program in the Wnt/beta-catenin signaling-ablated cortex. Thus, beta-catenin signaling controls the expression of a set of genes that appear to act downstream of canonical Wnt signaling to regulate the stage-specific production of appropriate progenitor numbers, neuronal subpopulations, and astroglia in the forebrain.