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 humans2,3,4, but have little effect on the brains of mice5,6,7,8,9; 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 diversity12,13,14 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 primates12,13,14,15,16. 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.
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We thank the late R. W. Guillery, who first introduced ferrets as a model for developmental neuroscience; J. K. Joung for advice on genome editing; J. Bond for the ASPM antibody; L. Vasung, P. Herman, J. Neil and C. D. Kroenke for advice on ferret brain MRI; A. Lee, the G. M. Church laboratory (S. Biwas), the S. McCarroll laboratory (S. Burger), the P. Kharchenko laboratory (J. Fan), and the R. Satija laboratory (A. Butler) for advice on scRNA-seq; S. Wasiuk, E. Feiner, A. S. Kamumbu and M. Lee for technical assistance; Marshall BioResources for animal husbandry; and E. Pollack and the veterinary staff at Boston Children’s Hospital and Yale School of Medicine for surgical support. Animal silhouettes in Fig. 1 were designed by Freepik from https://www.flaticon.com/. This work was supported by P30NS052519 (F.H. and Yale’s QNMR Core Center), 2R01MH067528 (F.H.), 1R24MH114805 (X.P.), R21HD083956 (K.I.), R01EB017337 (P.E.G.), R24HL123482 (J.F.E.), 5R01NS032457 (C.A.W.), 5R21NS091865 (B.-I.B.) and the Allen Discovery Center program through The Paul G. Allen Frontiers Group. C.A.W. is an Investigator of the Howard Hughes Medical Institute.
Nature thanks S. Juliano, F. Tissir and the other anonymous reviewer(s) for their contribution to the peer review of this work.