Cells, Vol. 13, Pages 1882: Loss of Dnah5 Downregulates Dync1h1 Expression, Causing Cortical Development Disorders and Congenital Hydrocephalus

Cells, Vol. 13, Pages 1882: Loss of Dnah5 Downregulates Dync1h1 Expression, Causing Cortical Development Disorders and Congenital Hydrocephalus

Cells doi: 10.3390/cells13221882

Authors: Koichiro Sakamoto Masakazu Miyajima Madoka Nakajima Ikuko Ogino Kou Horikoshi Ryo Miyahara Kaito Kawamura Kostadin Karagiozov Chihiro Kamohara Eri Nakamura Nobuhiro Tada Akihide Kondo

Dnah5 is associated with primary ciliary dyskinesia in humans. Dnah5-knockout (Dnah5−/− mice develop acute hydrocephalus shortly after birth owing to impaired ciliary motility and cerebrospinal fluid (CSF) stagnation. In contrast to chronic adult-onset hydrocephalus observed in other models, this rapid ventricular enlargement indicates additional factors beyond CSF stagnation. Herein, we investigated the contributors to rapid ventricular enlargement in congenital hydrocephalus. Dnah5−/− mice were generated using CRISPR/Cas9. The expression of dynein, N-cadherin, and nestin in the cerebral cortex was assessed using microarrays and immunostaining. Real-time PCR and Western blotting were performed for gene and protein quantification, respectively. All Dnah5−/− mice developed hydrocephalus, confirmed by electron microscopy, indicating the absence of axonemal outer dynein arms. Ventricular enlargement occurred rapidly, with a 25% reduction in the number of mature neurons in the motor cortex. Dync1h1 expression was decreased, while cytoplasmic dynein levels were 56.3% lower. Levels of nestin and N-cadherin in the lateral ventricular walls decreased by 31.7% and 33.3%, respectively. Reduced cytoplasmic dynein disrupts neurogenesis and axonal growth and reduces neuron cortical density. Hydrocephalus in Dnah5−/− mice may result from cortical maldevelopment due to cytoplasmic dynein deficiency, further exacerbating ventricular enlargement due to CSF stagnation caused by impaired motile ciliary function.