Role of Notch/RBPjk signaling pathaway in embryonic hematopoiesis

Resumen

The process that gives rise to all the mature blood cells from the HSCs (Hematopoietic Stem Cells) is known as hematopoiesis. In the adult, hematopoiesis takes place in the bone marrow although the HSCs are likely generated during embryonic life (reviewed in Cumano and Godin, Ann. Rev. Immunol 2007). Mouse embryonic hematopoiesis starts at embryonic day 7-7.5 in the extraembryonic yolk sac, whereas intraembryonic hematopoiesis starts at 9.5 in the aorta surrounded by gonad and mesonephros (a region known as AGM). The current knowledge is that both hematopoietic tissues can generate either pre-HSCs or adult HSCs that will seed the fetal liver by day 12 (that expands the pool of HSCs) and finally, near birth, the bone marrow, which will sustain adult-life hematopoiesis (reviewed in Cumano and Godin, Ann. Rev. Immunol, 2007). The Notch signaling pathway regulates tissue homeostasis and development not only in the embryo but in the adult as well (reviewed in Lai, Development 2007). Notch controls proliferation, differentiation and cell death in a wide variety of tissues including the nervous system, the vascular system and the hematopoietic system. In the latter, Notch has been described to regulate HSC proliferation, cell fate decisions and inhibition/induction of programmed cell death by apoptosis (reviewed in Radtke, Febs Letters 2006). Our results from the analysis of knock-out mice for some of the members of the Notch signaling pathway such as RBPjk (Oka, Development 1995), Jagged1 (Xue, Hum Mol Genet 1999) and Jagged2 (Jiang, Genes Dev 1998) and the usage of pharmacological inhibitors such as DAPT or L-685, indicate that Notch is dispensable for yolk sac hematopoiesis, although induces cell death by apoptosis in the compartment of erythroid Ter119+ cells generated in this tissue (Robert-Moreno, Leukemia 2007). On the other hand, Notch signaling pathway is required for the generation of hematopoietic progenitors and HSCs in the AGM since directly regulates the expression of the hematopoietic transcription factor GATA2 (Robert-Moreno, Development 2005). Finally, we propose that Notch activation through the ligand Jagged1 (but not Jagged2) is required for the activation of GATA2 expression and the generation and/or amplification of a pool of HSCs with high repopulation ability (Robert-Moreno, manuscript in preparation).