title: Aneuploid cells are differentially susceptible to caspase-mediated death during embryonic cerebral cortical development.
abstract: Neural progenitor cells, neurons, and glia of the normal vertebrate brain are diversely aneuploid, forming mosaics of intermixed aneuploid and euploid cells. The functional significance of neural mosaic aneuploidy is not known; however, the generation of aneuploidy during embryonic neurogenesis, coincident with caspase-dependent programmed cell death (PCD), suggests that a cell's karyotype could influence its survival within the CNS. To address this hypothesis, PCD in the mouse embryonic cerebral cortex was attenuated by global pharmacological inhibition of caspases or genetic removal of caspase-3 or caspase-9. The chromosomal repertoire of individual brain cells was then assessed by chromosome counting, spectral karyotyping, fluorescence in situ hybridization, and DNA content flow cytometry. Reducing PCD resulted in markedly enhanced mosaicism that was comprised of increased numbers of cells with the following: (1) numerical aneuploidy (chromosome losses or gains); (2) extreme forms of numerical aneuploidy (>5 chromosomes lost or gained); and (3) rare karyotypes, including those with coincident chromosome loss and gain, or absence of both members of a chromosome pair (nullisomy). Interestingly, mildly aneuploid (<5 chromosomes lost or gained) populations remained comparatively unchanged. These data demonstrate functional non-equivalence of distinguishable aneuploidies on neural cell survival, providing evidence that somatically generated, cell-autonomous genomic alterations have consequences for neural development and possibly other brain functions.
authors.affiliation: Department of Molecular Biology, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Peterson
authors.forename: Amy H
authors.initials: AH
authors.lastname: Yang
authors.forename: Diane M
authors.initials: DM
authors.lastname: Bushman
authors.forename: Jurjen W
authors.initials: JW
authors.lastname: Westra
authors.forename: Yun C
authors.initials: YC
authors.lastname: Yung
authors.forename: Serena
authors.initials: S
authors.lastname: Barral
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Mutoh
authors.forename: Stevens K
authors.initials: SK
authors.lastname: Rehen
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3 / Q000235:genetics / Q000502:physiology; D053453:Caspase 9 / Q000235:genetics / Q000502:physiology; D020169:Caspases / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000201:enzymology; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008297:Male; D008677:Metaphase / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis / Q000502:physiology; D011247:Pregnancy; D019849:Sex Determination Processes / Q000502:physiology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D004247:DNA; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases