CCM-3/STRIPAK promotes seamless tube extension through endocytic recycling

Nat Commun. 2015 Mar 6;6:6449. doi: 10.1038/ncomms7449.

Abstract

The mechanisms governing apical membrane assembly during biological tube development are poorly understood. Here, we show that extension of the C. elegans excretory canal requires cerebral cavernous malformation 3 (CCM-3), independent of the CCM1 orthologue KRI-1. Loss of ccm-3 causes canal truncations and aggregations of canaliculular vesicles, which form ectopic lumen (cysts). We show that CCM-3 localizes to the apical membrane, and in cooperation with GCK-1 and STRIPAK, promotes CDC-42 signalling, Golgi stability and endocytic recycling. We propose that endocytic recycling is mediated through the CDC-42-binding kinase MRCK-1, which interacts physically with CCM-3-STRIPAK. We further show canal membrane integrity to be dependent on the exocyst complex and the actin cytoskeleton. This work reveals novel in vivo roles of CCM-3·STRIPAK in regulating tube extension and membrane integrity through small GTPase signalling and vesicle dynamics, which may help explain the severity of CCM3 mutations in patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Cycle Proteins / metabolism*
  • GTP-Binding Proteins / metabolism*
  • Golgi Apparatus / metabolism
  • Intellectual Disability / metabolism*
  • Intestines / growth & development
  • Micrognathism / metabolism*
  • Microscopy, Electron, Transmission
  • Microscopy, Interference
  • Morphogenesis / physiology*
  • RNA Interference
  • Ribs / abnormalities*
  • Ribs / metabolism
  • Signal Transduction / physiology*
  • Transport Vesicles / physiology*

Substances

  • Caenorhabditis elegans Proteins
  • Cell Cycle Proteins
  • cdc-42 protein, C elegans
  • GTP-Binding Proteins

Supplementary concepts

  • Cerebral Cavernous Malformations 3