Wiring the developing brain: The Rho GTPase signaling network in neurodevelopmental disorders

Human genetics has substantially advanced our understanding of the Rho GTPase signaling network in brain development and established its dysregulation as an important mechanism underlying neurodevelopmental disorders (NDDs). Through the spatiotemporal control of actin cytoskeleton dynamics, canonical and atypical Rho GTPases, together with their guanine nucleotide exchange factors, GTPase-activating proteins, guanine nucleotide dissociation inhibitors, and downstream effectors, regulate major stages of corticogenesis, including neural progenitor proliferation and polarity, neuronal migration, axonal and dendritic development, synapse formation, and circuit maturation. Recent genomic studies have expanded the spectrum of Rho GTPase-related disorders by identifying pathogenic variants in core pathway genes, including RAC1, RAC3, CDC42, RHOA, and RHOBTB2, as well as in regulators and pathway-associated genes such as TRIO, OPHN1, ARHGEF9, ARHGAP31, DENND5A, DENND5B, and AUTS2. These findings indicate that genetically heterogeneous conditions, including autism spectrum disorder, intellectual disability, developmental and epileptic encephalopathies, and structural brain abnormalities, converge on shared developmental processes governing cytoskeletal remodeling, neuronal morphogenesis, synaptic organization, and connectivity. In this Review, we integrate the molecular architecture of Rho GTPase signaling with its physiological roles throughout corticogenesis and link individual signaling modules and disease-associated genes to clinical phenotypes and experimentally validated pathogenic mechanisms. This framework highlights how disruption of distinct components of the Rho GTPase network produces overlapping neurodevelopmental phenotypes through perturbation of common cellular and developmental programs.