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

Abstract

Hydrocephalus is caused by the accumulation of cerebrospinal fluid 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 grey 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 cerebrospinal fluid 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.

Strain-specific differences in brain gene expression in a hydrocephalic mouse model with motile cilia dysfunction

“…Loss of Cfap221 in nm1054 mutant mice results in PCD characterized by hydrocephalus, male infertility and airway abnormalities due to ciliary dysfunction 20 , 23 , 37 , 38 . Although no strain-specific differences have been observed for the reproductive or respiratory phenotypes, the hydrocephalus is more severe on the B6 background than 129 despite defects in ependymal cilia-driven fluid flow on both backgrounds 23 . To identify gene expression differences that might influence susceptibility to severe hydrocephalus in nm1054 mice on the B6 and 129 backgrounds, we utilized a DNA microarray approach.…”

“…We have demonstrated that congenic mouse models of PCD lacking ciliary proteins CFAP221, CFAP54 and SPEF2 all have a severe hydrocephalus on the C57BL6/J (B6) background but not on 129S6/SvEvTac (129) or a mixed (B6x129)F1 background 20 – 22 , indicating strain specificity in susceptibility to severe PCD-associated hydrocephalus. While there are defects in cilia-driven fluid flow on both backgrounds, ventricular dilatation and secondary damage to surrounding brain tissue are consistently more severe in mutants on the B6 background 23 . These findings are consistent with reports of severe hydrocephalus in other PCD models on the B6 background and an absence of severe hydrocephalus in models on the 129 background 16 .…”

“…To begin to understand the genes and pathways underlying hydrocephalus susceptibility, we performed a DNA microarray analysis to identify strain-specific differences in gene expression in whole brains from wild type mice and nm1054 mice lacking ciliary protein CFAP221 (previously known as PCDP1), as the phenotypic differences have been well characterized and are particularly dramatic in this line 20 , 23 . Similar approaches have been effective at identifying strain-specific candidate genes and mechanisms influencing a variety of murine phenotypes, including susceptibility to infection 30 , craniofacial defects 31 , hypertension 32 , eye pigmentation defects 33 , alcohol sensitivity 34 , cigarette smoke sensitivity 35 and social behavior 36 .…”

Use of immunoproteomics to identify immunogenic proteins in a rat model of acute respiratory distress syndrome

“…Therefore, another protein identified in the present study, SPEF2, was of interest. SPEF2 is predominantly expressed in ciliated tissues, including lung, trachea, testis and brain tissue (36)(37)(38). It is required for ciliary motility and spermatogenesis, and the loss of SPEF2 function was reported to result in severe spermatogenic defects (36).…”

Decreased Levels of Nasal Nitric Oxide in Children With Midline Neuroanatomical Anomalies: A Possible Connection Between Ciliary Dysfunction and Isolated Nervous System Defects

“…9,32 Murine studies have shown that certain PCD strains develop M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 11 alterations in neuronal differentiation, microglial activation, and myelination. 33 Interestingly, hydrocephalus is not limited to disturbances of motile cilia, and is in fact often detected in patients with primary ciolipathies, such as orofacialdigital syndrome and Bardet-Biedl syndrome. This suggests that mutations hindering the normal ciliary function may indeed affect both motile and primary cilia.…”