Hydrocephalic Mouse Models Of Primary Ciliary Dyskinesia Have Strain Dependent Defects In Brain Morphology And Physiology

Congenital hydrocephalus results from accumulation of cerebrospinal fluid (CSF) and causes severe neurological damage, but the underlying causes are not well understood. Hydrocephalus is associated with primary ciliary dyskinesia (PCD), a pediatric syndrome caused by dysfunction of motile cilia that can also result in sinusitis, male infertility, and situs inversus. We have investigated the causes of hydrocephalus in mouse models of PCD lacking the Pcdp1 and Spef2 proteins. Both models develop gross, lethal hydrocephalus on the C57BL/6J (B6) background but not on 129S6/SvEvTac (129). Histological and immunohistochemical analyses demonstrate that both mutants on B6 have ventricular dilatation, sloughing of ciliated ependyma, disrupted axon myelination, and increased gliosis, indicating significant injury to the cerebral cortex. In contrast, both mutants on both the B6 and 129 backgrounds exhibit perturbed CSF flow despite an absence of substantial morphological defects on 129. These findings indicate that abnormal cilia‐driven flow is not the sole determinant of PCD‐associated hydrocephalus and suggest that there are genetic modifiers that generally influence susceptibility to congenital hydrocephalus. Grant Funding Source : Supported by the NIH (1P20GM103620‐01A1)