Support for the Selective Chromatid Segregation Hypothesis Advanced For the Mechanism of Left-Right Body Axis Development in Mice

Issue title: Stem Cells and Breast Cancer

Guest editors: Barbara K. Vonderhaar and Gilbert H. Smith

Article type: Research Article

Authors: Klar, Amar J.S.^{; *}

Affiliations: Gene Regulation and Chromosome Biology Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702-1201, USA

Correspondence: [*] Corresponding author: Amar J.S. Klar, Gene Regulation and Chromosome Biology Laboratory, NCI-Frederick, P.O. Box B, Bldg. 539, Ft. Detrick, Frederick, MD 21702-1201, USA. Tel.: +1 301 846 5916; Fax: +1 301 846 6911; E-mail: [email protected]

Abstract: The somatic DNA strand-specific imprinting to effect gene regulation and selective chromatid segregation model was previously proposed to produce developmentally nonequivalent sister cells in mitosis. Such a mechanism might explain generation of stem-cell pattern of cell division in eukaryotes. The developmentally controlled process involves a pair of homologous chromosomes at a specific cell division to establish embryonic left-right body axis asymmetry. As a result, visceral organs in the two sides of vertebrate's body develop asymmetrically. The model was specifically proposed to explain the well-known axis randomization phenotype of the left-right dynein mutant mice where one-half of animals develop with standard visceral organ's positioning and the balance develops with the inverted arrangement. The model postulated that the specific dynein, a microtubule-based molecular motor protein, promotes the selective chromatid segregation process in mitosis. Thus, random segregation involving sister chromatids of a pair of specific chromosomes leads to axis randomization of the mutant. Moreover, the model uniquely predicts that 50 percent mutant embryos should produce symmetrical cell divisions because of random segregation; consequently, their either visceral side would develop as mirror image of the other side resulting in embryonic lethality. In view of this prediction, validity of prominent body axis-determination models is scrutinized here. Results supporting the cell-type regulated chromosome 6 and chromosome 7 selective chromatids segregation phenomenon existing in mouse cells are reviewed. Published results with the mutant mice are consistent with the chromosome segregation model for axis determination.

Keywords: Biased DNA-strand segregation phenomenon, asymmetric cell division, epigenetic model for development, left/right axis determination, developmental disorders

DOI: 10.3233/BD-2008-29106

Journal: Breast Disease, vol. 29, no. 1, pp. 47-56, 2008