Kulkarni, S. S. | Search bioRxiv

bioRxiv2018

The Heterotaxy Gene, CCDC11, is Essential for Cytokinesis and Cell-Cell Adhesion Via RhoA Regulation

Mutations in CCDC11 have been identified in multiple patients with heterotaxy (Htx), a disorder of left-right (LR) patterning of the internal organs. In Xenopus, depletion of Ccdc11 causes defects in LR patterning, recapitulating the patient phenotype. Upon Ccdc11 depletion, normally monociliated cells of the Left-Right Organizer (LRO) exhibit multiple cilia per cell. Unexpectedly, we found that Ccdc11 is necessary for successful cytokinesis, and the multiciliation observed in Ccdc11-depleted cells was due to failed cytokinesis. Furthermore, CCDC11 depletion alters cell-cell adhesion with reduction in junctional localization of adhesion molecules. The small GTPase RhoA is critical for cytokinesis and cell-cell adhesion. Because the CCDC11 depletion phenotypes are reminiscent of RhoA loss of function, we investigated a possible connection to regulation of RhoA signaling. We demonstrate that CCDC11 is localized to the cytokinetic contractile ring overlapping with RhoA during cytokinesis and regulates total RhoA protein levels. Our results suggest that CCDC11 connects cytokinesis and LR patterning via RhoA regulation, providing a potential mechanism for heterotaxy disease pathogenesis.

cell biology↗

bioRxiv2017

WDR5 stabilizes actin architecture to promote multiciliated cell formation

HIGHLIGHTS O_LIWDR5 has an H3K4 independent role in the formation of multiciliated cells.\nC_LIO_LIWDR5 controls apical cell expansion, basal body patterning, and ciliogenesis in multiciliated cells.\nC_LIO_LIWDR5 localizes near the ciliary base where it connects basal bodies to F-actin.\nC_LIO_LIWDR5 stabilizes the apical actin network in multiciliated cells.\nC_LI\n\nSUMMARYThe actin cytoskeleton is critical to shape cells and pattern intracellular organelles to drive tissue morphogenesis. In multiciliated cells (MCCs), apical actin forms a lattice that drives expansion of the cell surface necessary to host hundreds of cilia. The actin lattice also uniformly distributes basal bodies across this surface. This apical actin network is dynamically remodeled, but the molecules that regulate its architecture remain poorly understood. We identify the chromatin modifier, WDR5, as a regulator of apical F-actin in multiciliated cells. Unexpectedly, WDR5 functions independently of chromatin modification in MCCs. Instead, we discover a scaffolding role for WDR5 between the basal body and F-actin. Specifically, WDR5 binds to basal bodies and migrates apically, where F-actin organizes around WDR5. Using a monomer trap for G-actin, we show that WDR5 stabilizes F-actin to maintain apical lattice architecture. In summary, we identify a novel, non-chromatin role for WDR5 in stabilizing F-actin in multiciliated cells.\n\nIN BRIEFKulkarni et al discover a chromatin independent function for WDR5 in multiciliated cell formation. WDR5 localizes to the base of cilia and functions as a scaffold between the basal bodies and the apical actin lattice. There, WDR5 stabilizes the actin lattice that allows multiciliated cells to expand their apical surface, pattern basal bodies, and generate hundreds of cilia.

developmental biology↗