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Endosomal trafficking defects alter neural progenitor proliferation and cause microcephaly

Author

Listed:
  • Jacopo A. Carpentieri

    (Institut Curie, PSL Research University, CNRS UMR144)

  • Amandine Cicco

    (Institut Curie, PSL Research University, CNRS UMR144)

  • Marusa Lampic

    (Institut Curie, PSL Research University, CNRS UMR144)

  • David Andreau

    (Institut Curie, PSL Research University, CNRS UMR144)

  • Laurence Maestro

    (Université de Paris)

  • Fatima El Marjou

    (Institut Curie, PSL Research University, CNRS UMR144)

  • Laure Coquand

    (Institut Curie, PSL Research University, CNRS UMR144)

  • Nadia Bahi-Buisson

    (INSERM U1163, Institut Imagine, Necker Hospital
    Pediatric Neurology, Necker Enfants Malades Hospital, Université de Paris)

  • Jean-Baptiste Brault

    (Institut Curie, PSL Research University, CNRS UMR144)

  • Alexandre D. Baffet

    (Institut Curie, PSL Research University, CNRS UMR144
    Institut national de la santé et de la recherche médicale (Inserm))

Abstract

Primary microcephaly and megalencephaly are severe brain malformations defined by reduced and increased brain size, respectively. Whether these two pathologies arise from related alterations at the molecular level is unclear. Microcephaly has been largely associated with centrosomal defects, leading to cell death. Here, we investigate the consequences of WDR81 loss of function, which causes severe microcephaly in patients. We show that WDR81 regulates endosomal trafficking of EGFR and that loss of function leads to reduced MAP kinase pathway activation. Mouse radial glial progenitor cells knocked-out for WDR81 exhibit reduced proliferation rate, subsequently leading to reduced brain size. These proliferation defects are rescued in vivo by expressing a megalencephaly-causing mutant form of Cyclin D2. Our results identify the endosomal machinery as an important regulator of proliferation rates and brain growth, demonstrating that microcephaly and megalencephaly can be caused by opposite effects on the proliferation rate of radial glial progenitors.

Suggested Citation

  • Jacopo A. Carpentieri & Amandine Cicco & Marusa Lampic & David Andreau & Laurence Maestro & Fatima El Marjou & Laure Coquand & Nadia Bahi-Buisson & Jean-Baptiste Brault & Alexandre D. Baffet, 2022. "Endosomal trafficking defects alter neural progenitor proliferation and cause microcephaly," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27705-7
    DOI: 10.1038/s41467-021-27705-7
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    1. Matthew B. Johnson & Xingshen Sun & Andrew Kodani & Rebeca Borges-Monroy & Kelly M. Girskis & Steven C. Ryu & Peter P. Wang & Komal Patel & Dilenny M. Gonzalez & Yu Mi Woo & Ziying Yan & Bo Liang & Ri, 2018. "Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size," Nature, Nature, vol. 556(7701), pages 370-375, April.
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