Lavado Alfonso, Ware Michelle, Paré Joshua, Cao Xinwei
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Development. 2014 Nov;141(21):4182-93. doi: 10.1242/dev.111260.
The corpus callosum connects cerebral hemispheres and is the largest axon tract in the mammalian brain. Callosal malformations are among the most common congenital brain anomalies and are associated with a wide range of neuropsychological deficits. Crossing of the midline by callosal axons relies on a proper midline environment that harbors guidepost cells emitting guidance cues to instruct callosal axon navigation. Little is known about what controls the formation of the midline environment. We find that two components of the Hippo pathway, the tumor suppressor Nf2 (Merlin) and the transcriptional coactivator Yap (Yap1), regulate guidepost development and expression of the guidance cue Slit2 in mouse. During normal brain development, Nf2 suppresses Yap activity in neural progenitor cells to promote guidepost cell differentiation and prevent ectopic Slit2 expression. Loss of Nf2 causes malformation of midline guideposts and Slit2 upregulation, resulting in callosal agenesis. Slit2 heterozygosity and Yap deletion both restore callosal formation in Nf2 mutants. Furthermore, selectively elevating Yap activity in midline neural progenitors is sufficient to disrupt guidepost formation, upregulate Slit2 and prevent midline crossing. The Hippo pathway is known for its role in controlling organ growth and tumorigenesis. Our study identifies a novel role of this pathway in axon guidance. Moreover, by linking axon pathfinding and neural progenitor behaviors, our results provide an example of the intricate coordination between growth and wiring during brain development.
胼胝体连接大脑半球，是哺乳动物大脑中最大的轴突束。胼胝体畸形是最常见的先天性脑异常之一，与多种神经心理缺陷相关。胼胝体轴突穿越中线依赖于一个合适的中线环境，该环境中含有发出引导信号以指导胼胝体轴突导航的路标细胞。关于是什么控制中线环境的形成，人们知之甚少。我们发现，Hippo信号通路的两个组成部分，即肿瘤抑制因子Nf2（Merlin）和转录共激活因子Yap（Yap1），在小鼠中调节路标细胞的发育和引导信号Slit2的表达。在正常脑发育过程中，Nf2抑制神经祖细胞中的Yap活性，以促进路标细胞分化并防止异位Slit2表达。Nf2缺失会导致中线路标畸形和Slit2上调，从而导致胼胝体发育不全。Slit2杂合性和Yap缺失均可恢复Nf2突变体中的胼胝体形成。此外，在中线神经祖细胞中选择性提高Yap活性足以破坏路标形成，上调Slit2并阻止中线穿越。Hippo信号通路以其在控制器官生长和肿瘤发生中的作用而闻名。我们的研究确定了该信号通路在轴突导向中的新作用。此外，通过将轴突寻路与神经祖细胞行为联系起来，我们的结果提供了一个大脑发育过程中生长与布线之间复杂协调的例子。
