Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size

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, Richard S. Smith, Manavi Chatterjee, Daniel Coman, Xenophon Papademetris, Lawrence H. Staib, Fahmeed Hyder, Joseph B. Mandeville, P. Ellen Grant, Kiho Im, Hojoong Kwak, John F. Engelhardt, Christopher A. Walsh () and Byoung-Il Bae ()
Additional contact information
Matthew B. Johnson: Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
Xingshen Sun: Center for Gene Therapy, University of Iowa
Andrew Kodani: Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
Rebeca Borges-Monroy: Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
Kelly M. Girskis: Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
Steven C. Ryu: Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
Peter P. Wang: Manton Center for Orphan Disease Research, 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
Yu Mi Woo: Cornell University
Ziying Yan: Center for Gene Therapy, University of Iowa
Bo Liang: Center for Gene Therapy, University of Iowa
Richard S. Smith: Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
Manavi Chatterjee: School of Medicine, Yale University
Daniel Coman: Yale University
Xenophon Papademetris: Yale University
Lawrence H. Staib: Yale University
Fahmeed Hyder: 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
Christopher A. Walsh: Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School
Byoung-Il Bae: Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School

Nature, 2018, vol. 556, issue 7701, 370-375

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41586-018-0035-0

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