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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Qian X., DeGennaro E. M., Talukdar M., Akula S. K., Lai A., Shao D. D., ...Daha Fazla

Developmental Cell, cilt.57, sa.20, ss.2381, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 57 Sayı: 20
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1016/j.devcel.2022.09.011
  • Dergi Adı: Developmental Cell
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Chemical Abstracts Core, EMBASE, MEDLINE
  • Sayfa Sayıları: ss.2381
  • Anahtar Kelimeler: apoptosis, cerebral cortex, congenital brain malformation, corpus callosum, development, genetics, kinesin, migration, organoid
  • Karadeniz Teknik Üniversitesi Adresli: Evet

Özet

© 2022 The Author(s)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.