Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size

• Published in: Nature (London) Vol. 556; no. 7701; pp. 370 - 375
• Main Authors: Johnson, Matthew B., Sun, Xingshen, Kodani, Andrew, Borges-Monroy, Rebeca, Girskis, Kelly M., Ryu, Steven C., Wang, Peter P., Patel, Komal, Gonzalez, Dilenny M., Woo, Yu Mi, Yan, Ziying, Liang, Bo, Smith, Richard S., Chatterjee, Manavi, Coman, Daniel, Papademetris, Xenophon, Staib, Lawrence H., Hyder, Fahmeed, Mandeville, Joseph B., Grant, P. Ellen, Im, Kiho, Kwak, Hojoong, Engelhardt, John F., Walsh, Christopher A., Bae, Byoung-Il
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2018; Nature Publishing Group
• Subjects: 13/106; 14/19; 14/63; 38/32; 38/39; 42/100; 42/109; 42/89; 45/41; 45/91; 59/57; 631/136/368/2430; 631/208/135; 631/378/1689/2608; 631/378/2571/2579; 631/532/2182; 82/29; 82/51; Amino Acid Sequence; Animals; Biodiversity; Biological Evolution; Brain; Calmodulin-Binding Proteins - deficiency; Calmodulin-Binding Proteins - metabolism; Cells (biology); Centrosome - metabolism; Cerebral cortex; Cerebral Cortex - anatomy & histology; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Disease Models, Animal; Divergence; Evolution; Female; Ferrets; Ferrets - anatomy & histology; Ferrets - genetics; Fetuses; Gene Deletion; Gene Editing; Gene expression; Gene Expression Regulation, Developmental; Gene Knockout Techniques; Genes; Genetic aspects; Genetic research; Genetically modified animals; Genetics; Genome editing; Genomes; Genomics; Germ-Line Mutation; Glial cells; Homology; Humanities and Social Sciences; Humans; Letter; Male; Mice; Microcephaly; Microcephaly - genetics; Microcephaly - pathology; Microencephaly; multidisciplinary; Mustela putorius furo; Mutation; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural stem cells; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Neurogenesis; Neuronal-glial interactions; Organ Size; Physiological aspects; Primates; Progenitor cells; Proteins; Radial glial cells; Resveratrol; Rodents; Science; Science (multidisciplinary); Subventricular zone; Transcription, Genetic; Ventricle; Weight reduction
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-018-0035-0

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 humans 2 – 4 , but have little effect on the brains of mice 5 – 9 ; this probably reflects evolutionarily divergent functions of ASPM 10 , 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 diversity 12 – 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 patients 3 , 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 primates 12 – 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. In a ferret model, the microcephaly-associated gene Aspm regulates cortical expansion by controlling the transition of ventricular radial glial cells to more differentiated cell types.