Congenital hydrocephalus is a major neurological disorder with high rates of morbidity and mortality; however, the underlying cellular and molecular mechanisms remain largely unknown. Reproducible animal models mirroring both embryonic and postnatal hydrocephalus are also limited. Here, we describe a new mouse model of congenital hydrocephalus through knockout of β-catenin in Nkx2.1-expressing regional neural progenitors. Progressive ventriculomegaly and an enlarged brain were consistently observed in knockout mice from embryonic day 12.5 through to adulthood. Transcriptome profiling revealed severe dysfunctions in progenitor maintenance in the ventricular zone and therefore in cilium biogenesis after β-catenin knockout. Histological analyses also revealed an aberrant neuronal layout in both the ventral and dorsal telencephalon in hydrocephalic mice at both embryonic and postnatal stages. Thus, knockout of β-catenin in regional neural progenitors leads to congenital hydrocephalus and provides a reproducible animal model for studying pathological changes and developing therapeutic interventions for this devastating disease.

先天性脑积水是一种主要的神经系统疾病，发病率和死亡率都很高；然而，潜在的细胞和分子机制在很大程度上仍然未知。反映胚胎和出生后脑积水的可重复动物模型也很有限。在这里，我们通过敲除Nkx2.1中的 β-连环蛋白描述了一种新的先天性脑积水小鼠模型-表达区域神经祖细胞。从胚胎第 12.5 天到成年期，在基因敲除小鼠中始终观察到进行性脑室扩大和大脑增大。转录组分析显示，在 β- 连环蛋白敲除后，心室区的祖细胞维持存在严重功能障碍，因此纤毛生物发生也存在严重功能障碍。组织学分析还揭示了脑积水小鼠在胚胎和出生后阶段的腹侧和背侧端脑的异常神经元布局。因此，区域神经祖细胞中 β- 连环蛋白的敲除会导致先天性脑积水，并为研究病理变化和开发针对这种破坏性疾病的治疗干预提供了可重复的动物模型。