Title | Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Qian, X, DeGennaro, EM, Talukdar, M, Akula, SK, Lai, A, Shao, DD, Gonzalez, D, Marciano, JH, Smith, RS, Hylton, NK, Yang, E, J Bazan, F, Barrett, L, Yeh, RC, R Hill, S, Beck, SG, Otani, A, Angad, J, Mitani, T, Posey, JE, Pehlivan, D, Calame, D, Aydin, H, Yesilbas, O, Parks, KC, Argilli, E, England, E, Im, K, Taranath, A, Scott, HS, Barnett, CP, Arts, P, Sherr, EH, Lupski, JR, Walsh, CA |
Journal | Dev Cell |
Volume | 57 |
Issue | 20 |
Pagination | 2381-2396.e13 |
Date Published | 2022 Oct 24 |
ISSN | 1878-1551 |
Keywords | Animals, Apoptosis, Brain, Focal Adhesion Protein-Tyrosine Kinases, Humans, Kinesins, Mice, Neurons |
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. |
DOI | 10.1016/j.devcel.2022.09.011 |
Alternate Journal | Dev Cell |
PubMed ID | 36228617 |
Grant List | R01 NS035129 / NS / NINDS NIH HHS / United States T32 GM007753 / GM / NIGMS NIH HHS / United States T32 GM144273 / GM / NIGMS NIH HHS / United States |
Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis.
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