Asymmetric Division, Stem Cells and the Immortal Strand Hypothesis

George Edward Parris


I have proposed a hypothetical mechanism for guiding the development of complex, multi-cellular organisms that relies only on coding intrinsic to each cell (The Master Development Program hypothesis in Biosciences Hypotheses 2:3-12. 2009).  An essential element in that mechanism is the ability of a de facto stem cell to differentiate into two different cell types and produce branches in the lines of cells without external cues or asymmetric environmental factors.  At this time, I want to focus on this important element in more detail because I have realized that although much research has been published on asymmetric division, very little of it focuses on the genome.  Moreover, the accepted mechanisms for asymmetric division imply that asymmetry is induced in the cytoplasm and that differentiation of the genomic programming follows asymmetric division.  In the mechanism I proposed and elaborate here, asymmetry is first induced in the tetraploid (G2) stage of the cell cycle of a de facto stem cell and then the cytoplasm responds to a new transcriptome.  The mechanism that I describe coincidentally supports the immortal strand hypothesis, which opines that the parental strand of DNA always ends up in the parental stem cell.  In the mechanism that I proposed and elaborate here, the parental DNA strand remains in the original stem cell because it defines the original stem cell, while the newly synthesized and differentially imprinted strand defines the character of a new cell type (the progenitor of a new cell line).  


asymmetric division, stem cell, differentiation, development


.Burton A, Torres-Padilla ME: Epigenetic reprogramming and development: a unique heterochromatin organization in the preimplantation mouse embryo. Brief Funct Genomics.

.Khavari DA, Sen GL, Rinn JL: DNA methylation and epigenetic control of cellular differentiation. Cell Cycle, 9(19):3880-3883.

.Gan Q, Yoshida T, McDonald OG, Owens GK: Concise review: epigenetic mechanisms contribute to pluripotency and cell lineage determination of embryonic stem cells. Stem Cells 2007, 25(1):2-9.

.Knoblich JA: Mechanisms of asymmetric stem cell division. Cell 2008, 132(4):583-597.

.Chartier NT, Hyenne V, Labbe JC: [Mechanisms of asymmetric cell division: from model organisms to tumorigenesis]. Med Sci (Paris), 26(3):251-257.

.Gonczy P: Mechanisms of asymmetric cell division: flies and worms pave the way. Nat Rev Mol Cell Biol 2008, 9(5):355-366.

.Parris GE: A hypothetical Master Development Program for multi-cellular orgnisms: Ontogeny and phylogeny. Biosciences Hypotheses 2009, 2:3-12.

.Parris GE: Developmental diseases and the hypothetical Master Development Program. Med Hypotheses, 74(3):564-573.

.Caley DP, Pink RC, Trujillano D, Carter DR: Long noncoding RNAs, chromatin, and development. ScientificWorldJournal, 10:90-102.

. Mattick JS: Deconstructing the dogma: a new view of the evolution and genetic programming of complex organisms. Ann N Y Acad Sci 2009, 1178:29-46.

.Mattick JS, Gagen MJ: The evolution of controlled multitasked gene networks: the role of introns and other noncoding RNAs in the development of complex organisms. Mol Biol Evol 2001, 18(9):1611-1630.

.Pandey RR, Kanduri C: Transcriptional and Posttranscriptional Programming by Long Noncoding RNAs. Prog Mol Subcell Biol, 51:1-27.

.Rapicavoli NA, Poth EM, Blackshaw S: The long noncoding RNA RNCR2 directs mouse retinal cell specification. BMC Dev Biol, 10:49.

.Sheik Mohamed J, Gaughwin PM, Lim B, Robson P, Lipovich L: Conserved long noncoding RNAs transcriptionally regulated by Oct4 and Nanog modulate pluripotency in mouse embryonic stem cells. RNA, 16(2):324-337.

.Matzke M, Kanno T, Huettel B, Daxinger L, Matzke AJ: Targets of RNA-directed DNA methylation. Curr Opin Plant Biol 2007, 10(5):512-519.

.Leung KN, Chamberlain SJ, Lalande M, Lasalle JM: Neuronal chromatin dynamics of imprinting in development and disease. J Cell Biochem, 112(2):365-373.

Mercer TR, Qureshi IA, Gokhan S, Dinger ME, Li G, Mattick JS, Mehler MF: Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation. BMC Neurosci, 11:14.

.Zeng X, Chen S, Huang H: Phosphorylation of EZH2 by CDK1 and CDK2: A possible regulatory mechanism of transmission of the H3K27me3 epigenetic mark through cell divisions. Cell Cycle, 10(4).

.Lew DJ, Burke DJ, Dutta A: The immortal strand hypothesis: how could it work? Cell 2008, 133(1):21-23.

.Conboy MJ, Karasov AO, Rando TA: High incidence of non-random template strand segregation and asymmetric fate determination in dividing stem cells and their progeny. PLoS Biol 2007, 5(5):e102.

.Shinin V, Gayraud-Morel B, Gomes D, Tajbakhsh S: Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nat Cell Biol 2006, 8(7):677-687.

.Fei JF, Huttner WB: Nonselective sister chromatid segregation in mouse embryonic neocortical precursor cells. Cereb Cortex 2009, 19 Suppl 1:i49-54.

.Kiel MJ, He S, Ashkenazi R, Gentry SN, Teta M, Kushner JA, Jackson TL, Morrison SJ: Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU. Nature 2007, 449(7159):238-242.

.Sotiropoulou PA, Candi A, Blanpain C: The majority of multipotent epidermal stem cells do not protect their genome by asymmetrical chromosome segregation. Stem Cells 2008, 26(11):2964-2973.

.Cairns J: Cancer and the immortal strand hypothesis. Genetics 2006, 174(3):1069-1072.

.Cairns J: Mutation selection and the natural history of cancer. Nature 1975, 255(5505):197-200.

.Karpowicz P, Morshead C, Kam A, Jervis E, Ramunas J, Cheng V, van der Kooy D: Support for the immortal strand hypothesis: neural stem cells partition DNA asymmetrically in vitro. J Cell Biol 2005, 170(5):721-732.

.Karpowicz P, Pellikka M, Chea E, Godt D, Tepass U, van der Kooy D: The germline stem cells of Drosophila melanogaster partition DNA non-randomly. Eur J Cell Biol 2009, 88(7):397-408.

.Tannenbaum E, Sherley JL, Shakhnovich EI: Evolutionary dynamics of adult stem cells: comparison of random and immortal-strand segregation mechanisms. Phys Rev E Stat Nonlin Soft Matter Phys 2005, 71(4 Pt 1):041914.

.Walters K: Colonic stem cell data are consistent with the immortal model of stem cell division under non-random strand segregation. Cell Prolif 2009, 42(3):339-347.


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