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Nature. 2018 Apr;556(7701):370-375. doi: 10.1038/s41586-018-0035-0. Epub 2018 Apr 11.

Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size.

Johnson MB1,2, Sun X3,4,5, Kodani A1,2, Borges-Monroy R1,2, Girskis KM1,2, Ryu SC1,2, Wang PP1,2, Patel K6, Gonzalez DM1,2, Woo YM7, Yan Z3,4,5, Liang B3,4,5, Smith RS1,2, Chatterjee M6, Coman D8,9,10, Papademetris X9,10,11, Staib LH10,11,12, Hyder F8,9,10,11, Mandeville JB13, Grant PE14, Im K14, Kwak H7, Engelhardt JF3,4,5, Walsh CA15,16, Bae BI17,18,19.

Author information

1
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
2
Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
3
Department of Anatomy and Cell Biology, Center for Gene Therapy, University of Iowa, Iowa City, IA, USA.
4
Center for Gene Therapy, University of Iowa, Iowa City, IA, USA.
5
National Ferret Resource and Research Center, University of Iowa, Iowa City, IA, USA.
6
Department of Neurosurgery, School of Medicine, Yale University, New Haven, CT, USA.
7
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA.
8
Magnetic Resonance Research Center (MRRC), Yale University, New Haven, CT, USA.
9
Quantitative Neuroscience with Magnetic Resonance (QNMR) Core Center, Yale University, New Haven, CT, USA.
10
Department of Radiology & Biomedical Imaging, Yale University, New Haven, CT, USA.
11
Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
12
Department of Electrical Engineering, Yale University, New Haven, CT, USA.
13
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.
14
Division of Newborn Medicine, Fetal Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
15
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. christopher.walsh@childrens.harvard.edu.
16
Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. christopher.walsh@childrens.harvard.edu.
17
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. byoung-il.bae@yale.edu.
18
Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. byoung-il.bae@yale.edu.
19
Department of Neurosurgery, School of Medicine, Yale University, New Haven, CT, USA. byoung-il.bae@yale.edu.

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.

PMID:
29643508
PMCID:
PMC6095461
DOI:
10.1038/s41586-018-0035-0
[Indexed for MEDLINE]
Free PMC Article

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