Discovery of the mitotic selective chromatid segregation phenomenon and its implications for vertebrate development

Abstract

The asymmetric cell division process is required for cellular differentiation and embryonic development. Recent evidence obtained in Drosophila and C. elegans suggest that this process occurs by non-equivalent distribution of proteins or mRNA (intrinsic factors) to daughter cells, or by their differential exposure to cell extrinsic factors. In contrast, haploid fission yeast sister cells developmentally differ by inheriting sister chromatids that are differentiated by epigenetic means. Specifically, the act of DNA replication at the mating-type locus in yeast switches it's alternate alleles only in one specific member of chromosome 2 sister chromatids in nearly every chromosome replication cycle. To employ this kind of mechanism for cellular differentiation, strictly based on Watson-Crick structure of DNA in diploid organism, selective segregation mechanism is required to coordinate distribution of potentially differentiated sister chromatids to daughter cells. Genetic evidence to this postulate was fortuitously provided by the analysis of mitotic recombinants of chromosome 7 in mouse cells. Remarkably, the biased segregation occurs in some cell types but not in others and the process seems to be chromosome-specific. This review summarizes the discovery of selective chromatid segregation phenomenon and it suggests that such a process of Somatic Sister chromatid Imprinting and Selective chromatid Segregation (SSIS model) might explain development in eukaryotes, such as that of the body axis left-right visceral organs laterality specification in mice.

Figure 1

Two theoretical possibilities of selective chromatid distribution of Chr. 7 in mouse cell mitoses. For clarity and brevity, chromosomal DNA strands found normally in the double helix configuration are presented as straight lines. The W and C strands are defined by their specific 5′–3′DNA sequence orientation. In the WW:CC designated pattern, both template [older] W [arbitrarily coloured green] strand-containing chromatids are segregated to one daughter cell and both older C [red] strand-containing chromatids are segregated to the other daughter cells to cause asymmetric cell division. Equivalent daughter cells are produced in the WC:WC segregation mode because both inherit WC′ plus W′C chromosomes.

Figure 2

The recombination model employed to discover the biased chromatid segregation phenomenon. Mitotic crossover at the loxp sites is experimentally induced by transiently expressing Cre recombinase in cells (modified from [^•,^•] refs.). The crossover event generates one chromatid with a functional hypoxanthine phosphoribosyl transferase minigene and those colonies inheriting the marker are selected by growing in an appropriate selective medium. The P and M allelic constitution is determined with Southern analysis. To obtain the result of all recombinants becoming homozygous for P and M alleles, as in ES and endoderm cells [Table 1], recombination must occur not in the G1 but in the G2 phase, only between specific non-sister chromatids [e.g. WC′ with W′C], and it must be followed by selective distribution of sister centromeres, as indicated in the drawing. Therefore, all M/M and P/P homozygous recombinants are interpreted to reflect the WW:CC segregation, and all P/M recombinants reflect the WC:WC segregation process. All notations are defined in Figure 1.