Abstract
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) andArp2/3 to thecadherin complex. Blocking Neogenin binding to the Cyfip1/Abi WRC subunit results in actin depolymerization, junctional collapse, and denudation of the postnatal ventricular zone. In theembryonic 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.
Highlights
Perinatal hydrocephalus, a prevalent neurodevelopmental condition, is characterized by ventromegaly due to an increase in cerebrospinal fluid (CSF) and is associated with severe intellectual impairment and motor dysfunction (Guerra et al, 2015; Kousi and Katsanis, 2016)
We demonstrate that the netrin/repulsive guidance molecules (RGMs) receptor, Neogenin, plays a pivotal role in the maintenance of adherens junction stability in the ventricular zone (VZ) and that its loss results in severe hydrocephalus and cortical heterotopias
This study has revealed an essential role for Neogenin-mediated recruitment of the WAVE regulatory complex (WRC) and Arp2/3 in promoting actin ring stability, adherens junction assembly, and VZ and ependymal integrity in the embryo and neonate, respectively
Summary
A prevalent neurodevelopmental condition, is characterized by ventromegaly due to an increase in cerebrospinal fluid (CSF) and is associated with severe intellectual impairment and motor dysfunction (Guerra et al, 2015; Kousi and Katsanis, 2016). Tight cell-to-cell adhesion between ependymal cells is essential for ventricular integrity and is mediated by cadherin-based adherens junctions situated at the subapical membrane (Guerra et al, 2015; Kousi and Katsanis, 2016). As a consequence of junctional failure, is emerging as a major cause of hydrocephalus (Guerra et al, 2015; Rodrıguez et al, 2012). Junctional instability leads to loss of adhesion, the collapse of RGC structure, disruption of the ventricular surface and radial migration. Despite the importance of adhesion in the maintenance of ventricular integrity, the molecular mechanisms governing RGC and ependymal cell adherens junction assembly and stabilization are poorly understood
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