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Peer-reviewedCC BY-NC-ND 4.0Nature Communications

NDE1-Mediated Regulation of Neural Progenitor Regional Identity and Its Implication in Microcephaly

  • Rami Yair Tshuva1,2
  • Jeyoon Bok3
  • Mio Nonaka1,2
  • Xufeng Xue3,4
  • Bidisha Bhattacharya1,2
  • Aditya Kshirsagar1
  • Tsviya Olender1
  • Miri Danan-Gotthold1
  • Tamar Sapir1,2
  • Jianping Fu3,5,6
  • Orly Reiner1,2
6 affiliations
  1. 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
  2. 2Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
  3. 3Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI USA
  4. 4Division of Developmental Biology, Center for Stem Cell and Organoid Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
  5. 5Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI USA
  6. 6Department of Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI USA
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Abstract

Despite their significance, the genetic and molecular bases of neurodevelopmental disorders remain poorly understood. In this study, using human brain organoids and mouse models, we show that loss of NDE1, a gene closely associated with microcephaly, disrupts progenitor identity, prolongs mitosis, and alters regional patterning in the forebrain. NDE1 knockout leads to a caudal identity shift of neural progenitor cells in the organoids and mouse brains, coinciding with aberrant ERK signaling. Notably, downstream activation of the ERK pathway restored rostral PAX6 expression in human brain organoids. Parallel analyses of Nde1 knockout mice confirmed disrupted regional patterning of the forebrain. Together, our data establish NDE1 as a critical regulator of early human brain regionalization and elucidate molecular mechanisms underlying the structural abnormalities observed in NDE1-associated microcephaly.

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Cite

BibTeXRIS
BibTeX
@article{tshuva2026nde1mediated,
  title = {{NDE1-Mediated Regulation of Neural Progenitor Regional Identity and Its Implication in Microcephaly}},
  author = {Rami Yair Tshuva and Jeyoon Bok and Mio Nonaka and Xufeng Xue and Bidisha Bhattacharya and Aditya Kshirsagar and Tsviya Olender and Miri Danan-Gotthold and Tamar Sapir and Jianping Fu and Orly Reiner},
  journal = {Nature Communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-78201-9},
  url = {https://doi.org/10.1038/s41467-026-78201-9},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - NDE1-Mediated Regulation of Neural Progenitor Regional Identity and Its Implication in Microcephaly
AU  - Rami Yair Tshuva
AU  - Jeyoon Bok
AU  - Mio Nonaka
AU  - Xufeng Xue
AU  - Bidisha Bhattacharya
AU  - Aditya Kshirsagar
AU  - Tsviya Olender
AU  - Miri Danan-Gotthold
AU  - Tamar Sapir
AU  - Jianping Fu
AU  - Orly Reiner
PY  - 2026
DA  - 2026/09/28
JO  - Nature Communications
DO  - 10.1038/s41467-026-78201-9
UR  - https://doi.org/10.1038/s41467-026-78201-9
AB  - Despite their significance, the genetic and molecular bases of neurodevelopmental disorders remain poorly understood. In this study, using human brain organoids and mouse models, we show that loss of NDE1, a gene closely associated with microcephaly, disrupts progenitor identity, prolongs mitosis, and alters regional patterning in the forebrain. NDE1 knockout leads to a caudal identity shift of neural progenitor cells in the organoids and mouse brains, coinciding with aberrant ERK signaling. Notably, downstream activation of the ERK pathway restored rostral PAX6 expression in human brain organoids. Parallel analyses of Nde1 knockout mice confirmed disrupted regional patterning of the forebrain. Together, our data establish NDE1 as a critical regulator of early human brain regionalization and elucidate molecular mechanisms underlying the structural abnormalities observed in NDE1-associated microcephaly.
SN  - 2041-1723
ER  -