Department of Neuroscience and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
Nat Neurosci. 2022 Apr;25(4):458-473. doi: 10.1038/s41593-022-01043-3. Epub 2022 Apr 4.
Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain-CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH.
脑积水的特征是脑室扩张，通常归因于脑脊液（CSF）稳态的原发性缺陷。尽管疾病异质性很大，但这促使 CSF 分流成为儿童脑外科的主要原因。在这项研究中，我们通过将人类大脑转录组学与 483 名先天性脑积水（CH）患者的全外显子组测序相结合，发现 CH 风险基因在胚胎神经上皮干细胞中存在汇聚。在所有 CH 风险基因中，TRIM71/lin-41 具有最多的新生突变，并且在神经上皮细胞中特异性表达。携带神经上皮细胞特异性 Trim71 缺失或 CH 特异性 Trim71 突变的小鼠表现出产前脑积水。CH 突变会破坏 TRIM71 与其 RNA 靶标的结合，导致神经上皮细胞过早分化和神经发生减少。皮质发育不良导致皮质顺应性增加和继发性脑室扩大，而 CSF 循环没有原发性缺陷。这些数据强调了精确调节神经上皮细胞命运对正常脑-CSF 生物力学的重要性，并支持基于临床相关神经祖细胞的 CH 范例。
