Assembly of the C1d projection of the central microtubule pair apparatus in mammalian motile cilia requires the ciliary protein CFAP54. Loss of the C1d projection in mice lacking CFAP54 impairs ciliary motility and cilia-driven fluid flow and results in a primary ciliary dyskinesia phenotype.
BackgroundLower airway abnormalities are common in patients with primary ciliary dyskinesia (PCD), a pediatric syndrome that results from structural or functional defects in motile cilia. Patients can suffer from recurrent bacterial infection in the lung, bronchiectasis, and respiratory distress in addition to chronic sinusitis, otitis media, infertility, and laterality defects. However, surprisingly little is known about the pulmonary phenotype of mouse models of this disorder.ResultsThe pulmonary phenotype of two mouse models of PCD, nm1054 and bgh, which lack Pcdp1 and Spef2, respectively, was investigated by histological and immunohistochemical analysis. In addition, both models were challenged with Streptococcus pneumoniae, a common respiratory pathogen found in the lungs of PCD patients. Histopathological analyses reveal no detectable cellular, developmental, or inflammatory abnormalities in the lower airway of either PCD model. However, exposure to S. pneumoniae results in a markedly enhanced inflammatory response in both models. Based on analysis of inflammatory cells in bronchoalveolar lavage fluid and flow cytometric analysis of cytokines in the lung, the bgh model shows a particularly dramatic lymphocytic response by 3 days post-infection compared to the nm1054 model or wild type animals.ConclusionsDefects in ciliary motility result in a severe response to pulmonary infection. The PCD models nm1054 and bgh are distinct and clinically relevant models for future studies investigating the role of mucociliary clearance in host defense.
Congenital hydrocephalus results from cerebrospinal fluid accumulation in the ventricles of the brain and causes severe neurological damage, but the underlying causes are not well understood. It is associated with several syndromes, including primary ciliary dyskinesia (PCD), which is caused by dysfunction of motile cilia. We previously demonstrated that mouse models of PCD lacking ciliary proteins CFAP221, CFAP54 and SPEF2 all have hydrocephalus with a strain-dependent severity. While morphological defects are more severe on the C57BL/6J (B6) background than 129S6/SvEvTac (129), cerebrospinal fluid flow is perturbed on both backgrounds, suggesting that abnormal cilia-driven flow is not the only factor underlying the hydrocephalus phenotype. Here, we performed a microarray analysis on brains from wild type and nm1054 mice lacking CFAP221 on the B6 and 129 backgrounds. Expression differences were observed for a number of genes that cluster into distinct groups based on expression pattern and biological function, many of them implicated in cellular and biochemical processes essential for proper brain development. These include genes known to be functionally relevant to congenital hydrocephalus, as well as formation and function of both motile and sensory cilia. Identification of these genes provides important clues to mechanisms underlying congenital hydrocephalus severity.
primary ciliary dyskinesia (pcD) is a genetically heterogeneous syndrome that results from defects in motile cilia. The ciliary axoneme has a 9 + 2 microtubule structure consisting of nine peripheral doublets surrounding a central pair apparatus (CPA), which plays a critical role in regulating proper ciliary function. We have previously shown that mouse models with mutations in cpA genes CFAP221, CFAP54, and SPEF2 have a PCD phenotype with defects in ciliary motility. In this study, we investigated potential genetic interaction between these cpA genes by generating each combination of double heterozygous and double homozygous mutants. no detectable cilia-related phenotypes were observed in double heterozygotes, but all three double homozygous mutant lines exhibit early mortality and typically develop severe PCD-associated phenotypes of hydrocephalus, mucociliary clearance defects in the upper airway, and abnormal spermatogenesis. Double homozygous cilia are generally intact and display a normal morphology and distribution. Spermiogenesis is aborted in double homozygotes, with an absence of mature flagella on elongating spermatids and epididymal sperm. These findings identify genetic interactions between CPA genes and genetic mechanisms regulating the cpA and motile cilia function. Primary ciliary dyskinesia (PCD) is a syndrome resulting from dysfunction of motile ciliary clearance in the respiratory system, the brain, the fallopian tube, and the embryonic node, as well as sperm flagellar motility 1-5. It is genetically heterogeneous and commonly inherited in an autosomal recessive manner, although mutations causing X-linked recessive and autosomal dominant inheritance have been reported 6-9. Approximately 1 in 16,000 children are affected and typically exhibit chronic upper and lower airway infection, otitis media, male infertility, and situs inversus. Neonatal respiratory distress, congenital heart defects, female infertility, and hydrocephalus are also associated at a lower frequency. The core, or axoneme, of the motile cilium has a 9 + 2 microtubule structure with nine doublets along the outer periphery surrounding a central pair apparatus (CPA) 4,10. Ciliary motility is generated by dynein arms associated with the outer microtubule doublets and is regulated by the CPA, radial spokes connecting the outer and central microtubules, and the dynein regulatory complex. The cilia on the embryonic node possess a 9 + 0 microtubule structure without a CPA. A substantial number of mouse models of PCD has helped uncover the role of novel genes in ciliary function and PCD pathogenesis 4,5. However, only a few studies have investigated epistatic interaction of these genes. Mice lacking dynein assembly factor coiled coil domain containing protein 40 (CCDC40) have situs inversus with randomized expression of left-right patterning marker NODAL during gastrulation 11,12. Homozygous mutants that are also heterozygous for a NODAL mutation fail to establish left isomerism or left-sided expression of NODAL 12 , demonstrating that ...
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