Novel lissencephaly-associated NDEL1 variant reveals distinct roles of NDE1 and NDEL1 in nucleokinesis and human cortical malformations

Meng Han Tsai, Hao Chen Ke, Wan Cian Lin, Fang Shin Nian, Chia Wei Huang, Haw Yuan Cheng, Chi Sin Hsu, Tiziana Granata, Chien Hui Chang, Barbara Castellotti, Shin Yi Lin, Fabio M. Doniselli, Cheng Ju Lu, Silvana Franceschetti, Francesca Ragona, Pei Shan Hou, Laura Canafoglia, Chien Yi Tung, Mei Hsuan Lee, Won Jing WangJin Wu Tsai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The development of the cerebral cortex involves a series of dynamic events, including cell proliferation and migration, which rely on the motor protein dynein and its regulators NDE1 and NDEL1. While the loss of function in NDE1 leads to microcephaly-related malformations of cortical development (MCDs), NDEL1 variants have not been detected in MCD patients. Here, we identified two patients with pachygyria, with or without subcortical band heterotopia (SBH), carrying the same de novo somatic mosaic NDEL1 variant, p.Arg105Pro (p.R105P). Through single-cell RNA sequencing and spatial transcriptomic analysis, we observed complementary expression of Nde1/NDE1 and Ndel1/NDEL1 in neural progenitors and post-mitotic neurons, respectively. Ndel1 knockdown by in utero electroporation resulted in impaired neuronal migration, a phenotype that could not be rescued by p.R105P. Remarkably, p.R105P expression alone strongly disrupted neuronal migration, increased the length of the leading process, and impaired nucleus–centrosome coupling, suggesting a failure in nucleokinesis. Mechanistically, p.R105P disrupted NDEL1 binding to the dynein regulator LIS1. This study identifies the first lissencephaly-associated NDEL1 variant and sheds light on the distinct roles of NDE1 and NDEL1 in nucleokinesis and MCD pathogenesis.

Original languageEnglish
Article number13
JournalActa Neuropathologica
Volume147
Issue number1
DOIs
StatePublished - Jun 2024

Keywords

  • DYNC1H1
  • Dynein
  • Interkinetic nuclear migration
  • LIS1
  • Lissencephaly
  • Microcephaly
  • Microlissencephaly
  • NDE1
  • NDEL1
  • Neuronal migration
  • Nucleokinesis
  • PAFAH1B1
  • Radial glial cell

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