Neogenin Recruitment of the WAVE Regulatory Complex to Ependymal and Radial Progenitor Adherens Junctions Prevents Hydrocephalus

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Conor J. O'Leary, Cathrin C. Nourse, Natalie K. Lee, Amanda White, Michael Langford, Kai Sempert, Stacey J. Cole, Helen M. Cooper
Denudation of the ependyma due to loss of cell adhesion mediated by cadherin-based adherens junctions is a common feature of perinatal hydrocephalus. Junctional stability depends on the interaction between cadherins and the actin cytoskeleton. However, the molecular mechanism responsible for recruiting the actin nucleation machinery to the ependymal junction is unknown. Here, we reveal that loss of the netrin/RGM receptor, Neogenin, leads to severe hydrocephalus. We show that Neogenin plays a critical role in actin nucleation in the ependyma by anchoring the WAVE regulatory complex (WRC) and Arp2/3 to the cadherin complex. Blocking Neogenin binding to the Cyfip1/Abi WRC subunit results in actin depolymerization, junctional collapse, and denudation of the postnatal ventricular zone. In the embryonic cortex, this leads to loss of radial progenitor adhesion, aberrant neuronal migration, and neuronal heterotopias. Therefore, Neogenin-WRC interactions play a fundamental role in ensuring the fidelity of the embryonic ventricular zone and maturing ependyma.

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Teaser

Loss of ependymal adhesion leads to hydrocephalus. O'Leary et al. show that adherens junction assembly relies on Neogenin recruitment of the WRC and Arp2/3 to promote actin polymerization and that its loss results in hydrocephalus. Neogenin therefore stabilizes ependymal junctions to buffer the forces generated by increasing CSF in the neonate.


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