Abstract
The murine basic helix-loop-helix transcription (bHLH) factor mouse atonal homolog 6 (Math6) is expressed in numerous organs and supposed to be involved in several developmental processes. However, so far neither all aspects nor the molecular mechanisms of Math6 function have been explored exhaustively. To analyze the in vivo function of Math6 in detail, we generated a constitutive knockout (KO) mouse (Math6−/−) and performed an initial histological and molecular biological investigation of its main phenotype. Pregnant Math6−/− females suffer from a disturbed early placental development leading to the death of the majority of embryos independent of the embryonic Math6 genotype. A few placentas and fetuses survive the severe uterine hemorrhagic events at late mid-gestation (E13.5) and subsequently develop regularly. However, these fetuses could not be born due to obstructions within the gravid uterus, which hinder the birth process. Characterization of the endogenous spatiotemporal Math6 expression during placenta development reveals that Math6 is essential for an ordered decidualization and an important regulator of the maternal-fetal endocrine crosstalk regulating endometrial trophoblast invasion and differentiation. The strongly disturbed vascularization observed in the maternal placenta appears as an additional consequence of the altered endocrine status and as the main cause for the general hemorrhagic crisis.
Highlights
At the beginning of mammalian life, the implantation of a fertilized blastocyst and the ordered development of a placenta are necessary for the establishment of a successful and productive pregnancy
At day E10.5 the phase of mid-gestation starts and all layers of the definitive chorioallantoic placenta are established consisting of the maternal part, called decidua, and the fetal part composed of the junctional zone with trophoblast giant cells, spongiotrophoblasts and glycogen trophoblasts, the labyrinth and the chorionic trophoblast at the base of the forming labyrinth
To achieve a functional KO, genomic Math[6] exon 1 was flanked by loxP-sites including the insertion of a FRT-flanked neomycin selection (Neo) cassette by classical gene targeting techniques in embryonic stem cells derived from C57Bl/6 J mice (Fig. 1)
Summary
At the beginning of mammalian life, the implantation of a fertilized blastocyst and the ordered development of a placenta are necessary for the establishment of a successful and productive pregnancy. At day E10.5 the phase of mid-gestation starts and all layers of the definitive chorioallantoic placenta are established consisting of the maternal part, called decidua, and the fetal part composed of the junctional zone with trophoblast giant cells, spongiotrophoblasts and glycogen trophoblasts, the labyrinth and the chorionic trophoblast at the base of the forming labyrinth. For a successful pregnancy in humans as well as in mice, remodeling of the maternal blood vessels is very important to supply the increasing need of nutrition for the growing embryo and fetus. Two characteristic features of spiral artery remodeling are the degradation of smooth muscle cells within the Tunica media and an increase in the vessel lumen size[9]. They undergo a structural renewal depending on trophoblast invasion[10]. The blood vessel system of the decidua expands by angiogenesis
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