神经黏附分子DSCAM缺失导致先天脑积水的机制研究

Hydrocephalus is a medical condition in which an abnormal accumulation of cerebrospinal fluid leads to dilation of cerebral ventricles. Congenital hydrocephalus is one of the most common neural developmental defects at birth, causing brain damage, mental and physical problems, and even death. However, the molecular mechanisms underlying pathogenesis of congenital hydrocephalus are largely unknown. In our previous study, we found that spontaneous DSCAM (Down syndrome cell adhesion molecule) mutant mice (DSCAMdel17) develop severe hydrocephalus with dilated lateral ventricles, reduced thickness of cortex and corpus callosum, as well as deformed hippocampus. In addition, DSCAMdel17 mutation leads to decreased motor function and motor learning in mice，indicating that DSCAM is a new candidate gene of hydrocephalus. To ascertain complete knockout of DSCAM and precise control of its expression at the tissue and cellular level, we made DSCAM conditional knockout mice. Using this animal model, we will further explore the molecular and cellular mechanism of DSCAM-deficiency induced hydrocephalus. Completion of this project will elucidate the role of DSCAM in the development of cerebral ventricles and cerebrospinal fluid circulation. It will also provide insight into the pathogenesis of congenital hydrocephalus.

先天脑积水是指在神经发育过程中脑脊液异常增多所导致的脑室病理性扩张。该病是最常见的新生儿神经系统畸形之一，严重影响了新生儿的脑实质发育和神经系统的正常功能，严重时甚至导致死亡。目前国际上对脑积水尤其是先天脑积水的发病机制尚不明确。申请人的前期工作表明，在小鼠中唐氏综合征相关黏附分子DSCAM的自发突变会导致先天脑积水的发生，同时伴有运动和学习记忆能力的显著下降，提示DSCAM与脑室管发育和脑脊液循环相关。为了实现对DSCAM表达的精准调控，深入研究DSCAM缺失导致先天脑积水发生的机制，我们构建了DSCAM条件敲除小鼠。运用这一自主动物模型，我们将从器官和组织、细胞等多层次、多角度研究DSCAM如何参与调控脑室管发育和脑脊液循环。这一基础研究将加深我们对先天脑积水在神经系统发育中器质性变化和功能性改变的物质基础和致病机理的认知，为该病的筛查、干预和防治提供一些实验和理论依据。

先天脑积水是指在神经发育过程中脑脊液异常增多所导致的脑室病理性扩张。该病是最常见的新生儿神经系统畸形之一，严重影响了新生儿的脑实质发育和神经系统的正常功能，严重时甚至导致死亡。目前国际上对脑积水尤其是先天脑积水的发病机制尚不明确。申请人的前期工作表明，在小鼠中唐氏综合征相关黏附分子DSCAM的自发突变（Dscamdel7-/-）会导致先天脑积水的发生，同时伴有运动和学习记忆能力的显著下降，提示DSCAM与脑室管发育和脑脊液循环相关。为了实现对DSCAM表达的精准调控，深入研究DSCAM缺失导致先天脑积水发生的机制，我们构建了DSCAM条件敲除小鼠（Dscamfl/fl）。我们的研究表明，Dscam缺失是导致Dscamdel7-/-和Dscamfl/fl；CMVCre小鼠发生脑积水的遗传因素。Dscam缺失后，中央导水管、中央管和脉络丛发育正常，脑积水是交通型。Dscam缺失后室管膜上皮的纤毛缺失，这是导致脑积水发生的直接原因。我们的研究揭示了Dscam缺失导致脑积水发生的细胞学机制，为进一步揭示其分子机制指出了方向，指明了室管膜上皮细胞纤毛发育对神经系统发育的重要性。这一基础研究加深了我们对先天脑积水在神经系统发育中器质性变化和功能性改变的物质基础和致病机理的认知，为该病的筛查、干预和防治提供了一些实验和理论依据。