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

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.

Orly Reiner is an incumbent of the Berstein-Mason professorial chair of Neurochemistry and the Head of the M. Judith Ruth Institute for Preclinical Brain Research. Tamar Sapir is the Incumbent of the Leir Research Fellow Chair in Autism Spectrum Disorder.

We thank the transgenic mouse facility and the caretaker, Tamir Moshe, at the Weizmann Institute. Activities in the Fu lab have been supported technically by the Michigan Medicine Microscopy Core for microscopy, the Michigan Advanced Genomics Core for scRNA-seq services, and the Michigan Lurie Nanofabrication Facility for microfabrication. This work was supported by the Israel Science Foundation (ISF grant 545/21), the United States-Israel Binational Science Foundation (BSF; Grant No. 2023009), the NSF-BSF Emerging Frontiers in Research and Innovation program (EFRI; NSF-BSF Grant No. 2024616), and the Israel Ministry of Innovation, Science and Technology (Grant No. 0005900).

Additional support was provided by the Azrieli Institute for Brain and Neural Sciences, the Maurice and Vivienne Wohl Biology Endowment, the Gladys Monroy and Larry Marks Center for Brain Disorders, the Advantage Trust, the Nella and Leon Benoziyo Center for Neurological Diseases, the David and Fela Shapell Family Center for Genetic Disorders Research, the Abish-Frenkel RNA Center, the Crown Human Genome Center, the Andrea L. and Lawrence A. Wolfe Family Center for Research on Neuroimmunology and Neuromodulation, the Monroy-Marks Integrative Center for Brain Disorder Research, the Weizmann Center for Research on Neurodegeneration, the Brenden-Mann Women’s Innovation Impact Fund, the Irving B. Harris Fund for New Directions in Brain Research, and the Irving Bieber, M.D., and Toby Bieber, M.D.

Further support was provided by the Leff Family, Barbara and Roberto Kaminitz, Sergio and Sonia Lozinsky, Debbie Koren, Jack and Lenore Lowenthal, and the Dears Foundation; by a research grant from the Estates of Ethel H. Smith, Gerald Alexander, Mr. and Mrs. Fishstrom, Norman Fidelman, Hermine Miller, and Olga Klein Astrachan; and by Ethel Lena Levy and the Selsky Memory Research Project.