Primary ciliary dyskinesia (PCD) is a genetically heterogeneous autosomal recessive disorder characterized by recurrent infections of the respiratory tract associated with abnormal function of motile cilia. Approximately half of PCD patients also have alterations in the left-right organization of internal organ positioning including situs inversus and situs ambiguous (Kartagener’s Syndrome, KS). Here we identify an uncharacterized coiled-coil domain containing protein (CCDC40) essential for correct left-right patterning in mouse, zebrafish and humans. Ccdc40 is expressed in tissues that contain motile cilia and mutation of Ccdc40 results in cilia with reduced ranges of motility. Importantly, we demonstrate that CCDC40 deficiency causes a novel PCD variant characterized by misplacement of central pair microtubules and defective axonemal assembly of inner dynein arms (IDAs) and dynein regulator complexes (DRCs). CCDC40 localizes to motile cilia and the apical cytoplasm and is responsible for axonemal recruitment of CCDC39, which is also mutated in a similar PCD variant.
During vertebrate gastrulation, an epithelial to mesenchymal transition (EMT) is necessary for migration of mesoderm from the primitive streak. We demonstrate that p38 MAP kinase and a p38-interacting protein (p38IP) are critically required for downregulation of E-cadherin during gastrulation. In an ENU-mutagenesis screen we identified the droopy eye (drey) mutation, which affects splicing of p38IP. p38IP(drey) mutant embryos display incompletely penetrant defects in neural tube closure, eye development, and gastrulation. A stronger allele (p38IP(RRK)) exhibits gastrulation defects in which mesoderm migration is defective due to deficiency in E-cadherin protein downregulation in the primitive streak. We show that p38IP binds directly to p38 and is required for p38 activation in vivo. Moreover, both p38 and p38IP are required for E-cadherin downregulation during gastrulation. Finally, p38 regulates E-cadherin protein expression downstream from NCK-interacting kinase (NIK) and independently of the regulation of transcription by Fibroblast Growth Factor (Fgf) signaling and Snail.
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