Ma Shang, Santhosh Devi, Kumar T Peeyush, Huang Zhen
Departments of Neuroscience and Neurology, University of Wisconsin-Madison, Madison, WI, 53705, USA; Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI53706, USA.
Departments of Neuroscience and Neurology, University of Wisconsin-Madison, Madison, WI, 53705, USA; Program in Genetics and Medical Genetics, University of Wisconsin-Madison, Madison, WI53706, USA.
Dev Cell. 2017 May 22;41(4):366-381.e4. doi: 10.1016/j.devcel.2017.04.014.
Intimate communication between neural and vascular cells is critical for normal brain development and function. Germinal matrix (GM), a key primordium for the brain reward circuitry, is unique among brain regions for its distinct pace of angiogenesis and selective vulnerability to hemorrhage during development. A major neonatal condition, GM hemorrhage can lead to cerebral palsy, hydrocephalus, and mental retardation. Here we identify a brain-region-specific neural progenitor-based signaling pathway dedicated to regulating GM vessel development. This pathway consists of cell-surface sphingosine-1-phosphate receptors, an intracellular cascade including Gα co-factor Ric8a and p38 MAPK, and target gene integrin β8, which in turn regulates vascular TGF-β signaling. These findings provide insights into region-specific specialization of neurovascular communication, with special implications for deciphering potent early-life endocrine, as well as potential gut microbiota impacts on brain reward circuitry. They also identify tissue-specific molecular targets for GM hemorrhage intervention.
神经细胞与血管细胞之间的密切交流对于正常的大脑发育和功能至关重要。生发基质（GM）是大脑奖赏回路的关键原基，在脑区中独一无二，因为其在发育过程中具有独特的血管生成速度以及对出血的选择性易损性。GM出血是一种主要的新生儿疾病，可导致脑瘫、脑积水和智力迟钝。在此，我们鉴定出一条基于脑区特异性神经祖细胞的信号通路，专门用于调节GM血管发育。该通路由细胞表面的1-磷酸鞘氨醇受体、包括Gα辅因子Ric8a和p38丝裂原活化蛋白激酶（p38 MAPK）的细胞内级联反应以及靶基因整合素β8组成，而整合素β8反过来又调节血管转化生长因子-β（TGF-β）信号传导。这些发现为神经血管交流的区域特异性特化提供了见解，对解读早期生命中的强效内分泌以及潜在的肠道微生物群对大脑奖赏回路的影响具有特殊意义。它们还确定了GM出血干预的组织特异性分子靶点。
