QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, September 15, 2004, 24(37):8090-8096; doi:10.1523/JNEUROSCI.2263-04.2004

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (18) Citing Articles via Google Scholar Google Scholar Articles by McConnell, M. J. Articles by Barlow, C. Search for Related Content PubMed PubMed Citation Articles by McConnell, M. J. Articles by Barlow, C.

 Previous Article  |  Next Article 

Neurobiology of Disease
Failed Clearance of Aneuploid Embryonic Neural Progenitor Cells Leads to Excess Aneuploidy in the Atm-Deficient But Not the Trp53-Deficient Adult Cerebral Cortex

Michael J. McConnell,^1,2,4 Dhruv Kaushal,^3,4 Amy H. Yang,^2,4 Marcy A. Kingsbury,⁴ Stevens K. Rehen,⁴ Kai Treuner,¹ Robert Helton,¹ Emily G. Annas,¹ Jerold Chun,^2,3,4 and Carrolee Barlow^1,3

¹The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, Graduate Programs in ²Biomedical Sciences and ³Neurosciences, and ⁴Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093

Aneuploid neurons populate the normal adult brain, but the cause and the consequence of chromosome abnormalities in the CNS are poorly defined. In the adult cerebral cortex of three genetic mutants, one of which is a mouse model of the human neurodegenerative disease ataxia-telangiectasia (A-T), we observed divergent levels of sex chromosome (XY) aneuploidy. Although both A-T mutated (Atm)- and transformation related protein 53 (Trp53)-dependent mechanisms are thought to clear newly postmitotic neurons with chromosome abnormalities, we found a 38% increase in the prevalence of XY aneuploidy in the adult Atm^-/- cerebral cortex and a dramatic 78% decrease in Trp53^-/- mutant mice. A similar 43% decrease in adult XY aneuploidy was observed in DNA repair-deficient Xrcc5^-/- mutants. Additional investigation found an elevated incidence of aneuploid embryonic neural progenitor cells (NPCs) in all three mutants, but elevated apoptosis, a likely fate of embryonic NPCs with severe chromosome abnormalities, was observed only in Xrcc5^-/- mutants. These data lend increasing support to the hypothesis that hereditary mutations such as ATM-deficiency, which render abnormal cells resistant to developmental clearance, can lead to late-manifesting human neurological disorders.

Key words: aneuploidy; neurodegeneration; development; apoptosis; ataxia-telangiectasia; DNA damage signaling

---

Received June 9, 2004; revised July 20, 2004; accepted July 25, 2004.

This article has been cited by other articles:

				S. L. Thompson and D. A. Compton Proliferation of aneuploid human cells is limited by a p53-dependent mechanism J. Cell Biol., February 8, 2010; 188(3): 369 - 381. [Abstract] [Full Text] [PDF]

				I. Y. Iourov, S. G. Vorsanova, T. Liehr, A. D. Kolotii, and Y. B. Yurov Increased chromosome instability dramatically disrupts neural genome integrity and mediates cerebellar degeneration in the ataxia-telangiectasia brain Hum. Mol. Genet., July 15, 2009; 18(14): 2656 - 2669. [Abstract] [Full Text] [PDF]

				S. Bauer and P. H. Patterson The cell cycle-apoptosis connection revisited in the adult brain J. Cell Biol., November 21, 2005; 171(4): 641 - 650. [Abstract] [Full Text] [PDF]

				M. A. Kingsbury, B. Friedman, M. J. McConnell, S. K. Rehen, A. H. Yang, D. Kaushal, and J. Chun Aneuploid neurons are functionally active and integrated into brain circuitry PNAS, April 26, 2005; 102(17): 6143 - 6147. [Abstract] [Full Text] [PDF]

				Y. Yang and K. Herrup Loss of Neuronal Cell Cycle Control in Ataxia-Telangiectasia: A Unified Disease Mechanism J. Neurosci., March 9, 2005; 25(10): 2522 - 2529. [Abstract] [Full Text] [PDF]

				S. K. Rehen, Y. C. Yung, M. P. McCreight, D. Kaushal, A. H. Yang, B. S. V. Almeida, M. A. Kingsbury, K. M. S. Cabral, M. J. McConnell, B. Anliker, et al. Constitutional Aneuploidy in the Normal Human Brain J. Neurosci., March 2, 2005; 25(9): 2176 - 2180. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help