Specification of embryonic polarity and pattern formation in multicellular organisms requires inductive signals from neighboring cells. One approach toward understanding these interactions is to study mutations that disrupt development. Here, we demonstrate that mesd, a gene identified in the mesoderm development (mesd) deletion interval on mouse chromosome 7, is essential for specification of embryonic polarity and mesoderm induction. MESD functions in the endoplasmic reticulum as a specific chaperone for LRP5 and LRP6, which in conjunction with Frizzled, are coreceptors for canonical WNT signal transduction. Disruption of embryonic polarity and mesoderm differentiation in mesd-deficient embryos likely results from a primary defect in WNT signaling. However, phenotypic differences between mesd-deficient and wnt3(-)(/)(-) embryos suggest that MESD may function on related members of the low-density lipoprotein receptor (LDLR) family, whose members mediate diverse cellular processes ranging from cargo transport to signaling.

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...

Congenital hydrocephalus is a relatively common and debilitating birth defect with several known physiological causes. Dysfunction of motile cilia on the ependymal cells that line the ventricular surface of the brain can result in hydrocephalus by hindering the proper flow of cerebrospinal fluid. As a result, hydrocephalus can be associated with primary ciliary dyskinesia, a rare pediatric syndrome resulting from defects in ciliary and flagellar motility. Although the prevalence of hydrocephalus in primary ciliary dyskinesia patients is low, it is a common hallmark of the disease in mouse models, suggesting that distinct genetic mechanisms underlie the differences in the development and physiology of human and mouse brains. Mouse models of primary ciliary dyskinesia reveal strain-specific differences in the appearance and severity of hydrocephalus, indicating the presence of genetic modifiers segregating in inbred strains. These models may provide valuable insight into the genetic mechanisms that regulate susceptibility to hydrocephalus under the conditions of ependymal ciliary dysfunction.