Ciliogenesis inCaenorhabditis elegansrequires genetic interactions between ciliary middle segment localized NPHP-2 (inversin) and transition zone-associated proteins

Abstract

SummaryThe cystic kidney diseases nephronophthisis (NPHP), Meckel-Gruber syndrome (MKS) and Joubert syndrome (JBTS) share an underlying etiology of dysfunctional cilia. Patients diagnosed with NPHP type II have mutations in the gene INVS (also known as NPHP2), which encodes inversin, a cilia localizing protein. Here, we show that the C. elegans inversin ortholog, NPHP-2, localizes to the middle segment of sensory cilia and that nphp-2 is partially redundant with nphp-1 and nphp-4 (orthologs of human NPHP1 and NPHP4, respectively) for cilia placement within the head and tail sensilla. nphp-2 also genetically interacts with MKS ciliopathy gene orthologs, including mks-1, mks-3, mks-6, mksr-1 and mksr-2, in a sensilla-dependent manner to control cilia formation and placement. However, nphp-2 is not required for correct localization of the NPHP-and MKS-encoded ciliary transition zone proteins or for intraflagellar transport (IFT). We conclude that INVS/NPHP2 is conserved in C. elegans and that nphp-2 plays an important role in C. elegans cilia by acting as a modifier of the NPHP and MKS pathways to control cilia formation and development.

Cell- and subunit-specific mechanisms of CNG channel ciliary trafficking and localization inC. elegans

“…The region of TAX-2::GFP localization was instead reminiscent of the Inversin compartment observed in several cilia types in vertebrates (Shiba et al, 2009;Zhao and Malicki, 2011). As in mammalian cells, the Inversin homolog NPHP-2 is localized to the middle segment in C. elegans sensory cilia and has a role in placement of the transition zone (Warburton-Pitt et al, 2012). We found that localization of TAX-2::GFP in AWB cilia overlapped almost fully with that of NPHP-2::mCherry (Fig.…”

“…NPHP-2/Inversin contains an ankyrin repeat domain implicated in protein-protein interactions Mosavi et al, 2004;Warburton-Pitt et al, 2012). The ankyrin repeat domain of Inversin has been shown to be sufficient for ciliary localization of Inversin in nodal but not kidney cilia in mice, and rescues the left-right asymmetry defects of Inversin mutants (Watanabe et al, 2003).…”

Conserved Ankyrin Repeat Proteins and Their NIMA Kinase Partners Regulate Extracellular Matrix Remodeling and Intracellular Trafficking inCaenorhabditis elegans

“…Ankyrin repeat domains are important for protein-protein interactions and can serve as molecular scaffolds (Mosavi et al 2004;Voronin and Kiseleva 2008;Hollenbeck et al 2012). Based on reciprocal BLAST and OrthoList (Shaye and Greenwald 2011), MLT-4 is orthologous to human inversin (INVS), and more similar in amino acid sequence than a previously reported INVS ortholog, NPHP-2 ( Figure S1 and Figure S2) (Warburton-Pitt et al 2012). Unlike MLT-4, however, INVS contains a C-terminal region that is largely intrinsically disordered.…”

Cilia and coordination of signaling networks during heart development

“…[47][48][49][50][51] As an example, NPHP proteins, the nephrocystins, critically regulate the recruitment and access of proteins to the cilium, such as through the formation of ciliary gating complexes. [52][53][54][55][56][57][58][59][60][61] In this regard, NPHP2/inversin recruits and anchors NPHP3, NPHP9/Nek8, and the newly identified NPHP protein, Anks6, to a distinct region in the proximal cilium, the inversin compartment, and integrity of this module is essential for correct laterality establishment in organisms from zebrafish to humans. 15,[62][63][64][65][66][67][68] Inversin was first discovered for its role in L-R establishment 62 and, presumably, the inversin compartment impinges on the function of motile and/or sensory cilia at the embryonic node, 67,69 which is critical in breaking the embryonic bilateral symmetry through the generation of a net leftward flow of the embryonic fluid during gastrulation 8 (see also below).…”