Molecular regulation of hematopoietic stem cell self-renewal and differentiation

Danislav Spassov, James M. Abdullah, Ronald G. Nachtman, Roland Jurecic

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Recent studies have revealed several evolutionarily conserved genes that may be essential for regulation of stem cell self-renewal and differentiation in multicellular organisms ranging from invertebrates to humans and plants. Drosophila gene Piwi and its homologs in C. elegant (PRG-1, PRG-2) and plant A rabidopsis (ZW1LLE) are required for asymmetric division of germline stem celis (GSCs) to produce and maintain a daughter GSC and for meristemal cell maintenance. The RNA-binding protein Pumilio and the zinc-finger protein Nanos represent another class of evolutionarily conserved genes required for asymmetric division of GSC and differentiation of the stem cell progeny in Drosophila and C, elegans. Described function and evolutionary conservation of these genes raise an interesting posibility that they may play a role in self-renewal of somatic stem cells such as hematopoietic stem cells (HSC). To elucidate that we have used degenerate PCR and RTPCR to identify and define expresion of mouse homologs of Piwi, Pumilio and Nanos in mouse HSC' and progenitors. Here we describe cloning and expression analysis of two mouse Pumilio homologs, named Pumml and Pumrnl. Pumml and Pumm2 are highly conserved genes with 8 Pumilio RNA-binding domains at the C-terminus. Both are expressed throughout mouse embryonic development, and in a variety of adult mouse tissues (brain, heart, kidney, liver, lung, lymph node, mammary gland, muscle, spleen, testis, thymus, thyroid). During embryonic blood cell development Pumm genes are transcribed at higher level in mouse fetal liver HSC (Sea-1 c-WrAA4. Lin cells) than in progenitor cells (AA4.1 ). In adult mice expression of Pumm genes is downregulated as mouse BM HSC (Rh-123lowSca-rc-far Lin and Lin Sca-l+ cells) differentiate into progenitors (Lin Sea-1+), and is still detectable in various stages of lymphoid and myeloid cell development. Full length cDNAs have also been assembled for two homologous human genes, named Pumhl and Pumhl and the analysis of their tissue and hematopoietic expression pattern is in progress. To elucidate Pumm function in vitro the effect of overexpression of truncated Pumm forms on differentiation potential of pluripotent progenitor cell line EML Cl will be studied. To study the in vivo role of Pumml and Pumm2 in HSC and progenitor cell differentiation, we have determined the gene structure and are preparing targeting constructs to generate knockout mice.

Original languageEnglish (US)
Pages (from-to)69a
Issue number11 PART I
StatePublished - Dec 1 2000

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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