Arrested hematopoiesis and vascular relaxation defects in mice with a mutation in Dhfr

Julie A.I. Thoms, Kathy Knezevic, Jia Jenny Liu, Elias N. Glaros, Thuan Thai, Qiao Qiao, Heather Campbell, Deborah Packham, Yizhou Huang, Peter Papathanasiou, Robert Tunningley, Belinda Whittle, Amanda W.S. Yeung, Vashe Chandrakanthan, Luke Hesson, Vivien Chen, Jason W.H. Wong, Louise E. Purton, Robyn L. Ward, Shane R. Thomas*John E. Pimanda

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    5 Citations (Scopus)

    Abstract

    Dihydrofolate reductase (DHFR) is a critical enzyme in the folate metabolism pathway and also plays a role in regulating nitric oxide (NO) signaling in endothelial cells. Although both coding and noncoding mutations with phenotypic effects have been identified in the human DHFR gene, no mouse model is currently available to study the consequences of perturbing DHFR in vivo. In order to identify genes involved in definitive hematopoiesis, we performed a forward genetic screen and produced a mouse line, here referred to as Orana, with a point mutation in the Dhfr locus leading to a Thr136Ala substitution in the DHFR protein. Homozygote Orana mice initiate definitive hematopoiesis, but expansion of progenitors in the fetal liver is compromised, and the animals die between embryonic day 13.5 (E13.5) and E14.5. Heterozygote Orana mice survive to adulthood but have tissue-specific alterations in folate abundance and distribution, perturbed stress erythropoiesis, and impaired endothelium-dependent relaxation of the aorta consistent with the role of DHFR in regulating NO signaling. Orana mice provide insight into the dual roles of DHFR and are a useful model for investigating the role of environmental and dietary factors in the context of vascular defects caused by altered NO signaling.

    Original languageEnglish
    Pages (from-to)1222-1236
    Number of pages15
    JournalMolecular and Cellular Biology
    Volume36
    Issue number8
    DOIs
    Publication statusPublished - 2016

    Fingerprint

    Dive into the research topics of 'Arrested hematopoiesis and vascular relaxation defects in mice with a mutation in Dhfr'. Together they form a unique fingerprint.

    Cite this