Aug 2026· Frontiers in Cell and Developmental Biology· Vol 14· 0 citations· 244 references
Medicine
TL;DR
The molecular mechanisms that enable dyneins, kinesins, and myosins to function as regulators of cortical development are reviewed and the causal relationship between disruptions to the non-transport functions of motor proteins and cortical developmental disorders is focused on.
Abstract
Cerebral cortex development is a tightly coordinated sequence of interconnected processes: proliferation of neural progenitors, neuronal migration, neurite differentiation, axonal pathfinding, and synaptogenesis. Traditionally, motor proteins–dyneins, kinesins, and myosins–have been viewed as molecules mediating intracellular transport along the cytoskeleton. Nevertheless, data accumulated over the past decade provide compelling evidence for a fundamentally different, non-transport role of these proteins in nervous system development. This review systematizes current understanding of the non-transport functions of motor proteins at key stages of corticogenesis. We review the molecular mechanisms that enable dyneins, kinesins, and myosins to function as regulators of cortical development. We focus specifically on the causal relationship between disruptions to the non-transport functions of motor proteins and cortical developmental disorders, including microcephaly, lissencephaly, and agenesis of the corpus callosum.
The potential role of ribonucleoprotein-based transport as a primary mechanism driving circRNA localization is explored and how such spatial distribution influences synaptic plasticity and post-transcriptional gene regulation is examined.
Nicolò Salvi, M. Morlando· Non-Coding RNA· 0 citations
The development and maintenance of the nervous system depend on a tightly regulated intracellular transport network in which kinesin superfamily (KIF) motor proteins drive microtubule-based delivery of synaptic vesicle precursors, organelles, mRNAs, and signaling components along axons and dendrites. Disruption of this machinery underlies a clinically heterogeneous spectrum of neurodevelopmental disorders (NDDs), including intellectual disability, epilepsy, autism spectrum disorder, microcephaly, malformations of cortical development, spasticity, and axonal neuropathy. Here, we synthesize current knowledge on how kinesin dysfunction shapes neurodevelopment. We outline the physiological roles of kinesins in neuronal polarity, organelle and mitochondrial positioning, synaptogenesis, and progenitor division, and survey principal disease-associated genes, including KIF1A, KIF5A, KIF7, KIF11, KIF2A, KIF5C, and emerging members such as KIF14, KIF15, and KIF16B. We detail how distinct pathogenic mechanisms, such as loss of motility, impaired cargo coupling, motor hyperactivity, mitotic spindle defects, and disrupted ciliary signaling, converge on shared cellular endpoints, and how tubulin isotypes and posttranslational modifications further modulate motor output. In this review, we discuss translational implications, including variant-resolved diagnosis and precision strategies to restore transport, dampen pathological hyperactivity, or stabilize the microtubule track. Collectively, these advances reframe kinesinopathies as mechanistically stratified disorders of neuronal transport.
Mohammad Sadegh Shams Nosrati, Morteza Doustmohammadi, Alireza Dostmohammadi et al.· Current Issues in Molecular...· 0 citations
The survival motor neuron (SMN) protein is an essential and highly versatile assembly factor that coordinates RNA metabolism and ribonucleoprotein (RNP) complex formation across multiple cellular compartments. Although SMN is required for the survival of virtually all cell types, its deficiency disproportionately affects α-motor neurons, causing their selective degeneration and giving rise to spinal muscular atrophy (SMA). Once viewed primarily as a motor neuron disease, SMA is now understood to be a multi-systemic disorder in which cell-intrinsic dysfunction extends to skeletal muscle, inflammatory glial cells, and metabolic organs. This review examines the regulatory mechanisms that control SMN protein stability, collectively termed proteostasis, with a focus on how post-translational modifications coordinate with the ubiquitin-proteasome system and the autophagy-lysosomal pathway to govern protein turnover and clearance. We also address the emerging concept of gene dosage sensitivity, including the underappreciated paradox that therapeutic SMN overexpression can be as harmful as deficiency, producing distinct toxicities in both neuromuscular and peripheral tissues. Finally, we highlight the need for next-generation combination therapies that integrate genetic modifiers, targeted degradation strategies, and post-translational regulators to maintain SMN levels within the narrow physiological range required for safety and efficacy.
Bradley R. Smith, Rachel Massalee, Mason Mayer et al.· Frontiers in Cellular Neuros...· 0 citations
Proper nervous system development is critical for brain function, and deficits in neural development are implicated in many brain disorders. Neurons are distinctly polarized cells where mRNA can be transported to distal structures like axons and dendrites. Recent discoveries of widespread mRNA chemical modifications raise the question of their post-transcriptional regulatory role in brain development and function. N6-methyladenosine (m6A), installed by the METTL3/METTL14 methyltransferase complex, is the most prevalent internal mRNA modification, influencing stability, translation, splicing, and localization. However, the impact of m6A modification on RNA transport in developing neurons is not well understood. In this study, we find that the ablation of Mettl14 in postmitotic neurons leads to impaired axonal projection during corticogenesis. RNA-seq and single-molecule in situ hybridization reveal mislocalization of mRNAs in neurites of neurons with m6A loss-of-function. Furthermore, m6A-SAC-seq to identify a single nucleotide resolution m6A maps in the perinatal brain uncovers m6A-tagged transcripts associated with synapse organization, mRNA processing, and axonogenesis. We also identify YTHDF2 as the reader protein responsible for mRNA transport in callosal projection axons. YTHDF2 interacts with motor proteins, translational regulators, and microtubules to facilitate distal transport of m6A-tagged mRNA. Our data suggest that FMRP may serve as a context-guiding interactor that reshapes the YTHDF2 complex by recruiting specific cofactors and motor proteins, thereby promoting transport rather than degradation of m⁶A-tagged transcripts. Together, these findings provide insight into the epitranscriptomic mechanisms governing axon projection and guidance during mammalian cortical neurogenesis. Precise mRNA transport into neurites is essential for neural circuit formation. Here, the authors show that m6A RNA marks recruit YTHDF2-associated transport machinery that favors transport over degradation, localizing selected mRNAs to neurites to promote cortical axon projection.
Bonsang Koo, Ajeet Kumar, H. Hwang et al.· Nature Communications· 0 citations
The cellular distribution of mitochondria in response to stress and local energy needs is governed by the relative activities of the microtubule-based molecular motors kinesin and dynein. The mechanism for switching between these two opposite polarity microtubule motors remains unknown. Here, we coupled a cellular synthetic cargo transport assay with AlphaFold2-guided mutagenesis to identify a regulatory helix in the mitochondrial adaptor protein (TRAK) that mediates switching between kinesin- and dynein-driven transport. Differences in the helix sequence explained why two near-identical TRAK isoforms transported mitochondria in predominantly opposite directions. Phosphorylation of the regulatory helix by stress-activated kinases caused the activation of dynein and dissociation of kinesin. Our results reveal a molecular mechanism for coordinating the directional transport of mitochondria in response to intracellular signals.
C. Gladkova, Maria G Paez-Segala, W. Grant et al.· Science· 0 citations
Proper neocortex formation relies on the precisely regulated migration of neurons into distinct cortical layers. This process requires the timely surface expression of receptors that decode extracellular guidance cues. Yet, the molecular machinery governing receptor trafficking in migrating neurons remains largely unclear. Here, we identified the motor protein myosin Va (Myo5a) as a key regulator of Neuropilin-1 (Nrp1) trafficking in the early postnatal neocortex. Both male and female mice were used for this study. Myo5a localized to the apical dendrites of superficial layer neurons, with expression increasing during cortical maturation. Functional inhibition of Myo5a led to a terminal translocation defect in superficial layer neurons, thereby preventing their proper entry into NeuN-negative regions of the neocortex. Additionally, Myo5a inhibition led to Nrp1 accumulation within the Golgi apparatus and a significant reduction in its surface expression. Remarkably, overexpression of Nrp1 or VLDLR fully rescued the terminal translocation defects and dendritic abnormalities caused by Myo5a inhibition, demonstrating that Myo5a-dependent Nrp1 trafficking underlies proper Reelin receptor availability during this process. Overall, these results reveal a pivotal Myo5a-Nrp1 trafficking pathway that governs the final stage of neuronal migration, offering a molecular mechanism for the spatial and temporal regulation of receptor dynamics essential for precise cortical layering.Significance Statement Proper neocortex formation is essential for establishing functional brain circuits; however, the mechanisms by which migrating neurons interpret extracellular cues remain poorly understood. This study identified the motor protein Myo5a as a key regulator of the cell-surface expression of the Reelin coreceptor Nrp1 during the final phase of neuronal migration. Myo5a inhibition disrupts Nrp1 trafficking to the plasma membrane , leading to terminal translocation defects and abnormal dendritic development. Overexpression of Nrp1 or VLDLR fully rescues both phenotypes, indicating that Myo5a-dependent Nrp1 trafficking is essential for proper Reelin receptor availability at the cell surface. These findings reveal a previously unrecognized mechanism that enables neurons to respond properly to Reelin signaling, thus ensuring precise cortical layer formation during brain development.
Takao Kohno, Rimi Okino, Minqi Li et al.· Journal of Neuroscience· 0 citations
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