Strain-dependent brain defects in mouse models of primary ciliary dyskinesia with mutations in Pcdp1 and Spef2

Hydrocephalus is caused by the accumulation of cerebrospinal fluid (CSF) in the cerebral ventricular system which results in an enlargement of the cranium due to increased intraventricular pressure. The increase in pressure within the brain typically results in sloughing of ciliated ependymal cells, loss of cortical gray matter, and increased gliosis. Congenital hydrocephalus is associated with several syndromes including primary ciliary dyskinesia (PCD), a rare, genetically heterogeneous, pediatric syndrome that results from defects in motile cilia and flagella. We have examined the morphological and physiological defects in the brains of two mouse models of PCD, nm1054 and bgh, which have mutations in Pcdp1 (also known as Cfap221) and Spef2, respectively. Histopathological and immunohistochemical analyses of mice with these mutations on the C57BL/6J and 129S6/SvEvTac genetic backgrounds demonstrate strain-dependent morphological brain damage. Alterations in astrocytosis, microglial activation, myelination, and the neuronal population were identified and are generally more severe on the C57BL/6J background. Analysis of ependymal ciliary clearance ex vivo and CSF flow in vivo demonstrate a physiological defect in nm1054 and bgh mice on both genetic backgrounds, indicating that abnormal cilia-driven flow is not the sole determinant of the severity of hydrocephalus in these models. These results suggest that genetic modifiers play an important role in susceptibility to severe PCD-associated hydrocephalus.