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; Byoung-Il Bae

doi:10.1038/s41586-018-0035-0

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Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size

Journal article

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Peer reviewed

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, …

Nature (London), Vol.556(7701), pp.370-375

04/2018

DOI: 10.1038/s41586-018-0035-0

PMCID: PMC6095461

PMID: 29643508

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https://www.ncbi.nlm.nih.gov/pmc/articles/6095461View

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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) , 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 , but have little effect on the brains of mice ; this probably reflects evolutionarily divergent functions of ASPM . 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 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 , 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 . 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.

Microcephaly - genetics

Ferrets - anatomy & histology

Humans

Nerve Tissue Proteins - deficiency

Cerebral Cortex - pathology

Male

Cerebral Cortex - metabolism

Nerve Tissue Proteins - chemistry

Gene Expression Regulation, Developmental

Gene Deletion

Microcephaly - pathology

Germ-Line Mutation

Female

Transcription, Genetic

Calmodulin-Binding Proteins - deficiency

Cerebral Cortex - anatomy & histology

Ferrets - genetics

Disease Models, Animal

Amino Acid Sequence

Organ Size

Calmodulin-Binding Proteins - metabolism

Gene Knockout Techniques

Nerve Tissue Proteins - genetics

Neural Stem Cells - pathology

Gene Editing

Centrosome - metabolism

Biological Evolution

Nerve Tissue Proteins - metabolism

Animals

Mice

Neural Stem Cells - metabolism

Details

Title: Subtitle: Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size
Creators: Matthew B Johnson - Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Xingshen Sun - National Ferret Resource and Research Center, University of Iowa, Iowa City, IA, USA
Andrew Kodani - Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Rebeca Borges-Monroy - Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Kelly M Girskis - Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Steven C Ryu - Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Peter P Wang - Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Komal Patel - Department of Neurosurgery, School of Medicine, Yale University, New Haven, CT, USA
Dilenny M Gonzalez - Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Yu Mi Woo - Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
Ziying Yan - National Ferret Resource and Research Center, University of Iowa, Iowa City, IA, USA
Bo Liang - National Ferret Resource and Research Center, University of Iowa, Iowa City, IA, USA
Richard S Smith - Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Manavi Chatterjee - Department of Neurosurgery, School of Medicine, Yale University, New Haven, CT, USA
Daniel Coman - Department of Radiology & Biomedical Imaging, Yale University, New Haven, CT, USA
Xenophon Papademetris - Department of Biomedical Engineering, Yale University, New Haven, CT, USA
Lawrence H Staib - Department of Electrical Engineering, Yale University, New Haven, CT, USA
Fahmeed Hyder - Department of Biomedical Engineering, Yale University, New Haven, CT, USA
Joseph B Mandeville - Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA
P Ellen Grant - Division of Newborn Medicine, Fetal Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Kiho Im - Division of Newborn Medicine, Fetal Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Hojoong Kwak - Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
John F Engelhardt - National Ferret Resource and Research Center, University of Iowa, Iowa City, IA, USA
Christopher A Walsh - Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. christopher.walsh@childrens.harvard.edu
Byoung-Il Bae - Department of Neurosurgery, School of Medicine, Yale University, New Haven, CT, USA. byoung-il.bae@yale.edu
Resource Type: Journal article
Publication Details: Nature (London), Vol.556(7701), pp.370-375
DOI: 10.1038/s41586-018-0035-0
PMID: 29643508
PMCID: PMC6095461
NLM abbreviation: Nature
ISSN: 0028-0836
eISSN: 1476-4687
Publisher: England
Grant note: P30 ES005605 / NIEHS NIH HHS R24 HL123482 / NHLBI NIH HHS F32 NS100338 / NINDS NIH HHS R01 EB017337 / NIBIB NIH HHS Howard Hughes Medical Institute R01 NS035129 / NINDS NIH HHS K99 NS112604 / NINDS NIH HHS P30 NS052519 / NINDS NIH HHS R01 MH067528 / NIMH NIH HHS R21 HD083956 / NICHD NIH HHS R01 NS032457 / NINDS NIH HHS R21 NS091865 / NINDS NIH HHS R24 MH114805 / NIMH NIH HHS
Language: English
Date published: 04/2018
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
Record Identifier: 9984025447702771

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