Architects of the Developing Brain: Cytoskeleton-Organizing Molecules in Neurodevelopmental Disorders

Different components of the cytoskeleton are very important determinants of brain development. They orchestrate multiple cellular processes involved in all phases of cerebral cortex development. In this review, we summarize current knowledge on the components of the cytoskeleton-microtubules, actin filaments, and intermediate filaments-and their roles in cortical development. We provide a detailed analysis of how cytoskeleton molecules control neuronal progenitor proliferation, neuronal migration, polarization, axon and dendrite specification and outgrowth, and synaptogenesis. We further examine how pathogenic variants in genes encoding cytoskeletal proteins or their regulators disrupt particular steps of neurogenesis and contribute to major neurodevelopmental disorders (NDDs). Focusing on NDDs such as microcephaly, lissencephaly, corpus callosum agenesis, and synaptopathies, we discuss consequences of cytoskeletal dysfunctions causing altered cellular behavior and clinical phenotypes. By linking molecular defects to developmental and phenotypic consequences, this review highlights the cytoskeleton as a central element in neurodevelopmental pathologies and underscores its potential as a target for future therapeutic strategies.