Abstract
Recurrent spontaneous abortion (RSA) is defined as the loss of three or more consecutive pregnancies during the first trimester of embryonic intrauterine development. This kind of human infertility is frequent among the general population since it affects 1 to 5% of women. In half of the cases the etiology remains unelucidated. In the present study, we used interspecific recombinant congenic mouse strains (IRCS) in the aim to identify genes responsible for embryonic lethality. Applying a cartographic approach using a genotype/phenotype association, we identified a minimal QTL region, of about 6 Mb on chromosome 1, responsible for a high rate of embryonic death (∼30%). Genetic analysis suggests that the observed phenotype is linked to uterine dysfunction. Transcriptomic analysis of the uterine tissue revealed a preferential deregulation of genes of this region compared to the rest of the genome. Some genes from the QTL region are associated with VEGF signaling, mTOR signaling and ubiquitine/proteasome-protein degradation pathways. This work may contribute to elucidate the molecular basis of a multifactorial and complex human disorder as RSA.
Highlights
Embryonic development in mammals begins from the female and male interaction which leads to the oocyte fertilization
Using interspecific recombinant congenic strains (IRCS) animals we have previously shown that 3 QTL of embryonic lethality mapped on a unique spretus fragment in 3 strains, 66H-MMU13, 66H-MMU1 and 135E
Creation of 66H-MMU1 Substrains We started our study using the 66H-MMU1 strain which harbors a high rate of embryonic lethality (24.6%) caused by the Led2 QTL [15]
Summary
Embryonic development in mammals begins from the female and male interaction which leads to the oocyte fertilization. The external cells of the blastocyst develop into the placenta, a pivotal organ which allows immune tolerance, bidirectional foeto-maternal exchanges and crucial synthesis of gestational hormones [1]. All these biological processes are required for the survival of every mammalian species, and logically, they underlie a high level of complexity. Dysfunctions in these processes can lead to infertility. In humans it is a considerable public health problem, affecting up to 15% of couples. Due to the number of factors involved in a successful reproductive process, the mechanistics of infertility are far to being completely understood
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