Aug 2026· iScience· Vol 29· 0 citations· 52 references
Medicine
TL;DR
This study indicates that KIF2C may regulate microtubule dynamics to control deep-layer cortical neuron number and organization and modulate neuronal projections and signaling pathways and provides a foundation for understanding the role of KIF2C in neural development.
Abstract
Summary The microtubule-depolymerizing kinesin family member 2C (KIF2C) is highly expressed in neurological tumors and has been implicated in central nervous system (CNS) and psychiatric conditions, but its functions in the CNS remain unclear. To investigate the role of KIF2C in vivo, we generated global Kif2c knockout mice. Kif2c knockout leads to cortical structural abnormalities, selective reduction of deep-layer TBR1 immunoreactivity, and impairments in motor coordination and spatial learning. Single-cell RNA sequencing reveals altered deep-layer neuronal composition, marked by decreased layer 5 intratelencephalic neurons and a relative increase in extratelencephalic projection neurons. Furthermore, Kif2c deficiency drives disorganization of synapse-related gene expression and correlates with widespread expression changes in key developmental signaling pathways. Overall, this study indicates that KIF2C may regulate microtubule dynamics to control deep-layer cortical neuron number and organization and modulate neuronal projections and signaling pathways. This work provides a foundation for understanding the role of KIF2C in neural development.
Findings establish OCNDS as a disorder of compartment-specific translational dysregulation driven by impaired CK2α–G3BP1 control of RNA granule homeostasis, and establish G3bp1 knockdown rescues translational and morphological phenotypes across all OCNDS alleles.
Results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.
Inés Martínez-Soria, Pol Picón-Pagès, A. P. Pérez González et al.· bioRxiv· 0 citations
Mutations in the molecular motor protein KIF1A result in a spectrum of neurodevelopmental and neurodegenerative disorders termed KIF1A-Associated Neurological Disorder (KAND). KIF1A mutations variably disrupt synaptic vesicle trafficking, but the effects of KIF1A mutations on other trafficking pathways remain unexplored. Autophagy is a conserved pathway required for neuronal homeostasis. We investigated the role of KIF1A in autophagy using gene-edited human IPSC-derived neurons. KIF1A loss inhibited the trafficking of ATG9, a transmembrane lipid scramblase necessary for autophagosome biogenesis. This deficit significantly reduced autophagosome biogenesis and the density of axonal autophagosomes. KIF1A loss also depleted lysosomes from the axon, inhibiting autophagosome maturation. In neurons gene-edited to heterozygously express a pathogenic variant linked to a Rett-like syndrome in KAND patients, we also noted significant deficits in autophagy and lysosomal trafficking. Together, these results suggest that KIF1A-mediated transport is critical to neuronal autophagy and that deficits in autophagy may contribute to pathogenesis in KAND. GRAPHICAL ABSTRACT
Carris Borland, Jacob Popolow, E. Holzbaur· bioRxiv· 0 citations
These findings identify ankyrin-G as a molecular bridge between excitatory neuronal activity, synaptic structure, and myelin-associated protein expression, revealing a pathway by which ANK3 variants may contribute to neuropsychiatric disease.
Sehyoun Yoon, Marc Dos Santos, Natalia Khalatyan et al.· Proceedings of the National...· 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 results suggest that β-catenin deficiency in forebrain excitatory neurons leads to fear conditioning impairment, which could be contributed by the diminished excitatory synaptic transmission in PFC resulting from disrupted synaptic gene expression.
Luis Gustavo Hernandez Carballo, Rachel Senek, Ksenia Novototskaya-Vlasova et al.· Brain Communications· 0 citations
