The atypical RHO-GTPase RND3/RHOE interacts with FLRT3 to regulate cortical migration and folding

Authors

Zammou, B., Marfull-Oromi, P., Aghrabatt, S., Nicholson-Sabate, N., Pampols, M., Vila, L., Berbeira-Santana, M., Fernandez, V., Nagerl, D., Chauhan, D., Dolcet, X., Encinas, M., Klein, R., Borrell, V., Seiradake, E., del Toro, D., Egea, J.

Abstract

Cortical gyrification, characterized by the formation of sulcal fissures and gyral peaks, is a distinctive feature of large mammalian brains and is associated with the emergence of higher cognitive functions. This contrasts with small mammals, like mice, which generally display smooth (lissencephalic) cortices. Gyrification results from the integration of several complex processes such as neuron progenitor amplification and migration. However, the underlying molecular mechanisms remain poorly understood. Here, we show that genetic ablation of Rnd3, encoding the atypical RHO-GTPase RND3/RHOE, induces spontaneous cortical sulci in a subset of mouse embryos without increasing neural progenitor amplification. Instead, RND3 regulates cortical neuron migration, as RND3 overexpression delays neuronal migration, whereas its loss accelerates this process. Similar phenotypes reported in the double Flrt1/3 mutants, suggested a functional interaction between the transmembrane FLRTs and RND3 during cortex development. We demonstrate that Rnd3 and Flrt3 are co-expressed in migrating cortical neurons and interact through a beta-strand-mediated binding mechanism, involving a conserved motif in RND3. Disruption of this motif abolishes FLRT3 binding, impairs RND3-mediated regulation of neuronal migration and promotes sulcus formation, indicating that FLRT3-RND3 suppresses cortical folding by regulating neuronal migration in mice. Consistently, Rnd3 expression is reduced in the outer subventricular zone of the prospective sulcal regions in the gyrencephalic ferret brain, supporting the notion that RND3 downregulation contributes to sulci development. Together, these findings identify FLRT3-RND3 signalling as a conserved negative regulator of cortical neuron migration and cortical folding.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 11 Jul 2026.

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