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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

This work was supported by the National Institutes of Health (HL074247 for M.D.F. and AA008769 for J.H.S.) and a Department of Veteran's Affairs Merit Review Grant (T.A.W.). L.L. was supported in part by an NIH postdoctoral NRSA training grant (HL007574.23).

We gratefully thank James Edwards and Tonora Archibald in the Children's Hospital Boston Pathology Department histology core facility, as well as Yu Yang in the Dana Farber—Partners Cancer Center in situ core facility, for their technical assistance and expertise. We thank Hannah Kinney and Robin Haynes for human brain sections. We also thank Steven Margossian for reading the manuscript, as well as Nancy Andrews and members of the Andrews and Fleming laboratories for unending discussion and suggestions.