Dysfunction of the proteoglycan Tsukushi causes hydrocephalus through altered neurogenesis in the subventricular zone in mice
Dysfunction of the proteoglycan Tsukushi causes hydrocephalus through altered neurogenesis in the subventricular zone in mice
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DOI：
10.1126/scitranslmed.aay7896
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发表时间：
2021-03-31
影响因子：
17.1
通讯作者：
Ohta, Kunimasa
中科院分区：
文献类型：
--
作者：
Ito, Naofumi;Riyadh, M. Asrafuzzaman;Ohta, Kunimasa
侧脑室（LV）两侧为脑室下区（SVZ），这是一个神经干细胞（NSC）龛，富含调节神经干细胞维持、增殖和神经元分化的外源性生长因子。脑室下区龛的调节异常会导致侧脑室扩张，即脑积水；然而，其潜在的病理机制尚不清楚。我们发现，侧脑室表面室管膜细胞及脑脊液中蛋白聚糖筑波素（TSK）的缺失，会致使小鼠出现伴有神经发育障碍样症状的脑积水。这些症状伴随着神经干细胞谱系分化和存活的改变、室管膜结构的破坏以及Wnt信号通路的失调。在脑积水患者中发现的多种TSK变体，在小鼠体内和体外均表现出生理活性降低。向TSK基因敲除小鼠的侧脑室内给予野生型TSK蛋白或Wnt信号通路拮抗剂（而非脑积水相关的TSK变体），可预防脑积水并维持脑室下区的神经发生。这些观察结果表明，TSK作为一种龛分子，在调节脑室下区神经干细胞的命运方面起着关键作用，并提示TSK可作为脑积水诊断和治疗的候选靶点。
The lateral ventricle (LV) is flanked by the subventricular zone (SVZ), a neural stem cell (NSC) niche rich in extrinsic growth factors regulating NSC maintenance, proliferation, and neuronal differentiation. Dysregulation of the SVZ niche causes LV expansion, a condition known as hydrocephalus; however, the underlying pathological mechanisms are unclear. We show that deficiency of the proteoglycan Tsukushi (TSK) in ependymal cells at the LV surface and in the cerebrospinal fluid results in hydrocephalus with neurodevelopmental disorder-like symptoms in mice. These symptoms are accompanied by altered differentiation and survival of the NSC lineage, disrupted ependymal structure, and dysregulated Wnt signaling. Multiple TSK variants found in patients with hydrocephalus exhibit reduced physiological activity in mice in vivo and in vitro. Administration of wild-type TSK protein or Wnt antagonists, but not of hydrocephalus-related TSK variants, in the LV of TSK knockout mice prevented hydrocephalus and preserved SVZ neurogenesis. These observations suggest that TSK plays a crucial role as a niche molecule modulating the fate of SVZ NSCs and point to TSK as a candidate for the diagnosis and therapy of hydrocephalus.