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Intrauterine lethality in Tfpi gene disrupted mice is differentially suppressed during mid‐ and late‐gestation by platelet TFPIα overexpression
Author(s) -
Siebert Amy E.,
Maroney Susan A.,
Martinez Nicholas D.,
Mast Alan E.
Publication year - 2021
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.15299
Subject(s) - tissue factor pathway inhibitor , biology , embryo , genetically modified mouse , transgene , andrology , embryogenesis , endocrinology , medicine , microbiology and biotechnology , coagulation , gene , tissue factor , genetics
Background Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein required for murine embryonic development. Intrauterine lethality of Tfpi −/− mice occurs at mid‐ and late gestation, the latter of which is associated with severe cerebrovascular defects. Megakaryocytes produce only the TFPIα isoform, which is stored within platelets and released upon activation. Objectives To examine biological activities of platelet TFPIα (pTFPIα) by characterizing effects of pTFPIα overexpression in Tfpi −/− mice. Methods Transgenic mice overexpressing pTFPIα were generated and crossed onto the Tfpi −/− background. Genetic and histological analyses of embryos were performed to investigate the function of pTFPIα during embryogenesis. Results The transgene (Tg) increased pTFPIα 4‐ to 5‐fold without altering plasma TFPI in adult Tfpi +/+ and Tfpi +/− mice but did not rescue Tfpi −/− mice to wean. Analyses of the impact of pTFPIα overexpression on Tfpi −/− survival, however, were complicated by linkage between the Tg integration site and the endogenous Tfpi locus on chromosome 2. Strain‐specific genetic interactions also modulated Tfpi −/− embryonic survival. After accounting for these underlying genetic factors, pTFPIα overexpression completely suppressed mid‐gestational lethality of Tfpi −/− embryos but had no effect on development of cerebrovascular defects during late gestation resulting in their lack of survival to wean. Conclusions pTFPIα overexpression rescued Tfpi −/− embryos from mid‐gestational but not late gestational lethality. The prevalence of underlying genetic factors complicating analyses within our study illustrates the importance of meticulously characterizing transgenic mouse models to avoid spurious interpretation of results.