Primary Ciliary Dyskinesia in Mice Lacking the Novel Ciliary Protein Pcdp1

Abstract

Primary ciliary dyskinesia (PCD) results from ciliary dysfunction and is commonly characterized by sinusitis, male infertility, hydrocephalus, and situs inversus. Mice homozygous for the nm1054 mutation develop phenotypes associated with PCD. On certain genetic backgrounds, homozygous mutants die perinatally from severe hydrocephalus, while mice on other backgrounds have an accumulation of mucus in the sinus cavity and male infertility. Mutant sperm lack mature flagella, while respiratory epithelial cilia are present but beat at a slower frequency than wild-type cilia. Transgenic rescue demonstrates that the PCD in nm1054 mutants results from the loss of a single gene encoding the novel primary ciliary dyskinesia protein 1 (Pcdp1). The Pcdp1 gene is expressed in spermatogenic cells and motile ciliated epithelial cells. Immunohistochemistry shows that Pcdp1 protein localizes to sperm flagella and the cilia of respiratory epithelial cells and brain ependymal cells in both mice and humans. This study demonstrates that Pcdp1 plays an important role in ciliary and flagellar biogenesis and motility, making the nm1054 mutant a useful model for studying the molecular genetics and pathogenesis of PCD.Primary ciliary dyskinesia (PCD), which was previously known as immotile cilia syndrome, affects approximately 1 in 16,000 newborn children worldwide and results from a defect in ciliary and flagellar motility (1,2,6,13,17,66). Affected individuals often suffer from bronchiectasis, chronic sinusitis, and neonatal respiratory distress. In addition, males are infertile, and many individuals have situs inversus, a complete reversal of left-right asymmetry. The triad of sinusitis, bronchiectasis, and situs inversus is commonly known as Kartagener's syndrome. Some individuals with PCD also develop hydrocephalus (3,15,18,28,32,70), otitis media (39,40,47), and retinitis pigmentosa (37,65,76).Motile cilia are located on the surface of many types of eukaryotic cells and have a variety of functions (18,22,36,46,60,63). For example, cilia on respiratory epithelial cells are responsible for movement of fluid and particles over the cell surface and are a critical component of host defense. Cilia on ependymal cells lining the ventricular surface of the brain facilitate cerebrospinal fluid flow, while those on the embryonic node play a critical role in left-right patterning during early development. The structurally related flagella are required for sperm motility.Motile cilia elongate from the basal bodies of epithelial, ependymal, or nodal cells (1,13,17,20,22,27,36,46,60,54). The core, or axoneme, of the cilia and flagella consists of a "9 ϩ 2" microtubule structure with a ring of nine microtubule doublets surrounding a central pair of single microtubules.Several accessory proteins are associated with the microtubule pairs, including radial spokes and dynein arms, which generate the motor force required for ciliary motility. Although motile, nodal cilia have a 9 ϩ 0 arrangement that lacks the central microtubule pair and resemble immot...

Static respiratory cilia associated with mutations in Dnahc11/DNAH11: A mouse model of PCD

“…We have not only confirmed that the iv model has static respiratory cilia at 37 • C, but that it develops PCD-related disease including rhinitis, sinusitis, and otitis media. Consistent with other PCD mouse models [Ibanez-Tallon et al, 2002;Lee et al, 2008;Tanaka et al, 2004], none of the mice in this study developed significant lung pathology. This is perhaps an agerelated phenomenon (our oldest mice were 42 weeks old), or lack of disease may be associated with the relatively sterile environment of the animal facilities as suggested for CF models [Davidson and Rolfe, 2001].…”

“…This mouse line has been constantly bred as a homozygous colony for over 50 years, demonstrating that it is robust, viable, and that it demands only normal husbandry, in contrast to the viability issues seen in other models including Dnahc5 [Tan et al, 2007], nm1054 [Lee et al, 2008] and the complex preparatory considerations associated with the Dnaic conditional mutant [Ostrowski et al, 2010]. We have not only confirmed that the iv model has static respiratory cilia at 37 • C, but that it develops PCD-related disease including rhinitis, sinusitis, and otitis media.…”

“…These mice, however, show loss of sperm tails and lethal anemia. Transgenic rescue demonstrated Pcdp1 (MGI: Gm101) to underlie the PCD-like symptoms and Steap3 the lethal anemia [Lee et al, 2008;Ohgami et al, 2005], permitting genetic rescue of the anemia. The Dnahc1 (MIM# 603332) null results in reduced tracheal cilia and sperm tail motility; however, no analysis of upper respiratory tract pathology was performed making it unclear how well this models PCD.…”

Sperm dysfunction and ciliopathy

“…One is Pcdp1, whose knockout results in hydrocephalus, male infertility, and slight defects in ciliary movement in trachea [183]. Studies in Chlamydomonas demonstrate that the Pcdp1 homolog, FAP221, is a CP protein that binds to calmodulin and is localized to the C1d projection [184].…”

Primary Ciliary Dyskinesia/Kartagener Syndrome - Clinical and Genetic Aspects

“…Clinical molecular genetic testing for primary ciliary dyskinesia is available for the most common mutations. Lee et al (2008) show that the PCD phenotypes of hydrocephalus, male infertility, and respiratory ciliary dysfunction result from the loss of a single, novel gene named primary ciliary dyskinesia protein 1 (Pcdp1). They also demonstrate expression of the gene in spermatogenic and motile ciliated cell types and show protein localization in flagella and motile cilia in both mice and humans.…”