Secretion of Reelin by blood vessels affects the formation of the cerebral cortex

在第一个神经元产生之前，发育中的前脑被血管包围。血管网络随后侵入胚胎前脑，新生神经元迁移形成六层，构成成人大脑皮层。虽然以前认为血管在发育过程中仅起支持作用，但现在广泛接受血管提供指导性信号来调节皮质神经元的产生和迁移。最近，血管发育缺陷被认为是神经发育起源的皮层病变的原因。我们发现血管分泌Reelin，这是一种蛋白质，在啮齿动物和人类大脑皮层的形成和连接中起着至关重要的作用，也与人类的神经发育障碍有关。虽然在人类和啮齿动物的血浆中检测到Reelin，但对其在大脑皮层形成中的意义和功能知之甚少。在这里，我们建议使用遗传策略在小鼠血管中特异性地去除Reelin，并分析大脑皮层的形成是如何受到影响的。此外，我们将使用小鼠模型，旨在阐明血管分泌Reelin并与发育中的大脑神经元交流的分子机制。因此，拟议的研究计划将探索血管分泌关键分子Reelin的新机制，以及大脑皮层形成过程中脉管系统和神经元之间的交流。这项工作可能会增强我们对大脑这一区域发育障碍的病因学的理解，如精神分裂症和自闭症。

The developing forebrain is surrounded by blood vessels before the first neurons are generated. Vascular networks subsequently invade the embryonic forebrain as newly born neurons migrate to form the six layers that will comprise the adult cerebral cortex. While it was previously believed that blood vessels only have a supportive role during development, it is now widely accepted that they provide instructive signals to regulate the generation and migration of cortical neurons. More recently, defective blood vessel development has been suggested to contribute to cortical pathologies of neurodevelopmental origin. We have found that blood vessels secrete Reelin, a protein which has a crucial role in the formation and connectivity of the rodent and human cerebral cortex, and which has also been linked to neurodevelopmental disorders in humans. While Reelin has been detected in human and rodent blood plasma, little is known about its significance and function in the formation of the cerebral cortex. Here, we propose to use genetic strategies in mice to remove Reelin specifically from blood vessels and analyse how the formation of the cerebral cortex is affected. Further, we will use mouse models in a strategy aimed to shed light on the molecular mechanisms by which blood vessels secrete Reelin and communicate with neurons in the developing brain. Thus, the proposed research programme will explore novel mechanisms that underlie the secretion of a key molecule, Reelin, by blood vessels and the communication between vasculature and neurons during the formation of the cerebral cortex. This work is likely to enhance our understanding of the aetiologies of developmental disorders of this area of the brain such as schizophrenia and autism.