Publication Date

10-24-2022

Journal

Develpmental Cell

DOI

10.1016/j.devcel.2022.09.011

PMID

36228617

PMCID

PMC10585591

PubMedCentral® Posted Date

10-12-2022

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Animals, Mice, Kinesins, Neurons, Focal Adhesion Protein-Tyrosine Kinases, Apoptosis, Brain

Abstract

Kinesins are canonical molecular motors but can also function as modulators of intracellular signaling. KIF26A, an unconventional kinesin that lacks motor activity, inhibits growth-factor-receptor-bound protein 2 (GRB2)- and focal adhesion kinase (FAK)-dependent signal transduction, but its functions in the brain have not been characterized. We report a patient cohort with biallelic loss-of-function variants in KIF26A, exhibiting a spectrum of congenital brain malformations. In the developing brain, KIF26A is preferentially expressed during early- and mid-gestation in excitatory neurons. Combining mice and human iPSC-derived organoid models, we discovered that loss of KIF26A causes excitatory neuron-specific defects in radial migration, localization, dendritic and axonal growth, and apoptosis, offering a convincing explanation of the disease etiology in patients. Single-cell RNA sequencing in KIF26A knockout organoids revealed transcriptional changes in MAPK, MYC, and E2F pathways. Our findings illustrate the pathogenesis of KIF26A loss-of-function variants and identify the surprising versatility of this non-motor kinesin.

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