Supplementary Material for: Wnt Signaling Regulates Intermediate Precursor Production in the Postnatal Dentate Gyrus by Regulating Cxcr4 Expression

Previous studies have examined the role of diverse signaling pathways in dentate neurogenesis, but how these signaling pathways are integrated remains unknown. Using mice that allow genetic manipulation of type 1 radial progenitors in the dentate, we show that forced induction of Wnt signaling leads to expansion of the intermediate progenitor cell (IPC) pool while selective activation of Sonic hedgehog (Shh) signaling drives neurogenesis without significant expansion of IPCs. Thus, both Wnt and Shh signaling are proneurogenic, but they act in distinct manners when their signaling is forced in subgranular zone radial progenitors. We examined potential targets of the Wnt pathway in these cells and found that Cxcr4 is a direct target of Lef1 in dentate gyrus progenitors and that loss of Cxcr4 in postnatal neurogenesis decreases the production of IPCs. This suggests that Wnt activation of dentate gyrus progenitors induces Cxcl12 signaling by regulating receptor expression. This study provides evidence that distinct morphogenic pathways have notably different roles in regulating ongoing dentate neurogenesis.既往研究已探讨了多种信号通路在齿状回神经发生（dentate neurogenesis）中的作用，但这些信号通路的整合机制仍未明确。本研究利用可对齿状回内1型放射状祖细胞进行遗传操作的小鼠模型，证实强制诱导Wnt信号通路激活可导致中间祖细胞（intermediate progenitor cell, IPC）池扩增，而选择性激活音猬因子（Sonic hedgehog, Shh）信号通路则可在不显著扩增IPC池的情况下促进神经发生。由此可见，Wnt与Shh信号通路均具有促神经发生作用，但当在颗粒下区放射状祖细胞中强制激活二者时，其发挥调控作用的方式截然不同。我们进一步检测了Wnt通路在这些细胞中的潜在靶标，发现Cxcr4是齿状回祖细胞中Lef1的直接靶基因，且在出生后神经发生过程中缺失Cxcr4会降低IPC的生成量。这表明，齿状回祖细胞的Wnt信号激活可通过调控受体表达诱导Cxcl12信号通路活化。本研究提供了证据表明，不同的形态发生信号通路在调控持续性齿状回神经发生过程中发挥着显著不同的作用。