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Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size

Author

Listed:
  • Matthew B. Johnson

    (Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
    Boston Children’s Hospital, Harvard Medical School)

  • Xingshen Sun

    (Center for Gene Therapy, University of Iowa
    University of Iowa
    University of Iowa)

  • Andrew Kodani

    (Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
    Boston Children’s Hospital, Harvard Medical School)

  • Rebeca Borges-Monroy

    (Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
    Boston Children’s Hospital, Harvard Medical School)

  • Kelly M. Girskis

    (Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
    Boston Children’s Hospital, Harvard Medical School)

  • Steven C. Ryu

    (Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
    Boston Children’s Hospital, Harvard Medical School)

  • Peter P. Wang

    (Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
    Boston Children’s Hospital, Harvard Medical School)

  • Komal Patel

    (School of Medicine, Yale University)

  • Dilenny M. Gonzalez

    (Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
    Boston Children’s Hospital, Harvard Medical School)

  • Yu Mi Woo

    (Cornell University)

  • Ziying Yan

    (Center for Gene Therapy, University of Iowa
    University of Iowa
    University of Iowa)

  • Bo Liang

    (Center for Gene Therapy, University of Iowa
    University of Iowa
    University of Iowa)

  • Richard S. Smith

    (Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
    Boston Children’s Hospital, Harvard Medical School)

  • Manavi Chatterjee

    (School of Medicine, Yale University)

  • Daniel Coman

    (Yale University
    Yale University
    Yale University)

  • Xenophon Papademetris

    (Yale University
    Yale University
    Yale University)

  • Lawrence H. Staib

    (Yale University
    Yale University
    Yale University)

  • Fahmeed Hyder

    (Yale University
    Yale University
    Yale University
    Yale University)

  • Joseph B. Mandeville

    (Massachusetts General Hospital)

  • P. Ellen Grant

    (Boston Children’s Hospital, Harvard Medical School)

  • Kiho Im

    (Boston Children’s Hospital, Harvard Medical School)

  • Hojoong Kwak

    (Cornell University)

  • John F. Engelhardt

    (Center for Gene Therapy, University of Iowa
    University of Iowa
    University of Iowa)

  • Christopher A. Walsh

    (Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
    Boston Children’s Hospital, Harvard Medical School)

  • Byoung-Il Bae

    (Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
    Boston Children’s Hospital, Harvard Medical School
    School of Medicine, Yale University)

Abstract

The human cerebral cortex is distinguished by its large size and abundant gyrification, or folding. However, the evolutionary mechanisms that drive cortical size and structure are unknown. Although genes that are essential for cortical developmental expansion have been identified from the genetics of human primary microcephaly (a disorder associated with reduced brain size and intellectual disability)1, studies of these genes in mice, which have a smooth cortex that is one thousand times smaller than the cortex of humans, have provided limited insight. Mutations in abnormal spindle-like microcephaly-associated (ASPM), the most common recessive microcephaly gene, reduce cortical volume by at least 50% in humans2–4, but have little effect on the brains of mice5–9; this probably reflects evolutionarily divergent functions of ASPM10,11. Here we used genome editing to create a germline knockout of Aspm in the ferret (Mustela putorius furo), a species with a larger, gyrified cortex and greater neural progenitor cell diversity12–14 than mice, and closer protein sequence homology to the human ASPM protein. Aspm knockout ferrets exhibit severe microcephaly (25–40% decreases in brain weight), reflecting reduced cortical surface area without significant change in cortical thickness, as has been found in human patients3,4, suggesting that loss of ‘cortical units’ has occurred. The cortex of fetal Aspm knockout ferrets displays a very large premature displacement of ventricular radial glial cells to the outer subventricular zone, where many resemble outer radial glia, a subtype of neural progenitor cells that are essentially absent in mice and have been implicated in cerebral cortical expansion in primates12–16. These data suggest an evolutionary mechanism by which ASPM regulates cortical expansion by controlling the affinity of ventricular radial glial cells for the ventricular surface, thus modulating the ratio of ventricular radial glial cells, the most undifferentiated cell type, to outer radial glia, a more differentiated progenitor.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:556:y:2018:i:7701:d:10.1038_s41586-018-0035-0
    DOI: 10.1038/s41586-018-0035-0
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    Cited by:

    1. Soraia Barão & Yijun Xu & José P. Llongueras & Rachel Vistein & Loyal Goff & Kristina J. Nielsen & Byoung-Il Bae & Richard S. Smith & Christopher A. Walsh & Genevieve Stein-O’Brien & Ulrich Müller, 2024. "Conserved transcriptional regulation by BRN1 and BRN2 in neocortical progenitors drives mammalian neural specification and neocortical expansion," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. 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.

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