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https://hdl.handle.net/2440/140771
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Type: | Journal article |
Title: | Arrested hematopoiesis and vascular relaxation defects in mice with a mutation in Dhfr |
Author: | Thoms, J.A.I. Knezevic, K. Liu, J.J. Glaros, E.N. Thai, T. Qiao, Q. Campbell, H. Packham, D. Huang, Y. Papathanasiou, P. Tunningley, R. Whittle, B. Yeung, A.W.S. Chandrakanthan, V. Hesson, L. Chen, V. Wong, J.W.H. Purton, L.E. Ward, R.L. Thomas, S.R. et al. |
Citation: | Molecular and Cellular Biology, 2016; 36(8):1222-1236 |
Publisher: | American Society for Microbiology |
Issue Date: | 2016 |
ISSN: | 0270-7306 1098-5549 |
Statement of Responsibility: | Julie A. I. Thoms ... Vashe Chandrakanthan ... et al. |
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. |
Keywords: | Amino Acid Sequence Amino Acid Substitution Animals Aorta Base Sequence Cell Line Folic Acid Hematopoiesis Homozygote Humans Liver Mice Mice, Inbred C57BL Models, Molecular Nitric Oxide Tetrahydrofolate Dehydrogenase |
Rights: | © 2016, American Society for Microbiology. All Rights Reserved. |
DOI: | 10.1128/MCB.01035-15 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1058508 http://purl.org/au-research/grants/nhmrc/1102589 http://purl.org/au-research/grants/nhmrc/1100495 http://purl.org/au-research/grants/nhmrc/1003339 http://purl.org/au-research/grants/nhmrc/1016847 http://purl.org/au-research/grants/arc/FT13010096 |
Published version: | http://dx.doi.org/10.1128/mcb.01035-15 |
Appears in Collections: | Research Outputs |
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