Early-onset ventriculomegaly and neuroimmune alterations in Hoatz-deficient mice

Hydrocephalus in mice is frequently associated with impaired motile cilia function. We previously reported that the loss of Hoatz, a motile cilia and flagella-associated gene, causes ventriculomegaly of variable severity. Here, we characterize the ventricular phenotype of Hoatz−/− mice using in vivo magnetic resonance imaging (MRI), histology, and transcriptomics. Severe hydrocephalus occurred in only 4.9% (4/82) of homozygotes. High-resolution MRI revealed a reproducible ~4.7-fold enlargement of the lateral and third ventricles, while overall brain size was preserved. Despite the modest degree of ventriculomegaly, detailed volumetric analyses demonstrated deformation of the surrounding brain parenchyma, most prominently affecting the hippocampus. Ventricular enlargement emerged rapidly during early postnatal development and was occasionally associated with periventricular edema. Morphological and transcriptomic analyses further revealed changes in hippocampal microglia consistent with an altered activation state. Collectively, these findings define Hoatz deficiency as a cause of early-onset ventriculomegaly of the lateral and third ventricles, characterized by preserved overall brain size and regional hippocampal deformation, and establish a complementary mouse model for investigating the consequences of altered cerebrospinal fluid dynamics.