To maintain tissue integrity during epithelial morphogenesis, adherens junctions (AJs) must resist the mechanical stresses exerted by dynamic tissue movements. Junctional stability is dependent on actomyosin contractility within the actin ring. Here we describe a novel function for the axon guidance receptor, Neogenin, as a key component of the actin nucleation machinery governing junctional stability. Loss of Neogenin perturbs AJs and attenuates junctional tension. Neogenin promotes actin nucleation at AJs by recruiting the Wave regulatory complex (WRC) and Arp2/3. A direct interaction between the Neogenin WIRS domain and the WRC is crucial for the spatially restricted recruitment of the WRC to the junction. Thus, we provide the first example of a functional WIRS–WRC interaction in epithelia. We further show that Neogenin regulates cadherin recycling at the AJ. In summary, we identify Neogenin as a pivotal component of the AJ, where it influences both cadherin dynamics and junctional tension.

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.