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

Thoms, Julie A. I., Knezevic, Kathy, Liu, Jia Jenny, Glaros, Elias N., Thai, Thuan, Qiao, Qiao, Campbell, Heather, Packham, Deborah, Huang, Yizhou, Papathanasiou, Peter, Tunningley, Robert, Whittle, Belinda, Yeung, Amanda W. S., Chandrakanthan, Vashe, Hesson, Luke, Chen, Vivien, Wong, Jason W. H., Purton, Louise E., Ward, Robyn L., Thomas, Shane R. and Pimanda, John E. (2016) Arrested hematopoiesis and vascular relaxation defects in mice with a mutation in Dhfr. Molecular and Cellular Biology, 36 8: 1222-1236. doi:10.1128/MCB.01035-15

Attached Files (Some files may be inaccessible until you login with your UQ eSpace credentials)
Name Description MIMEType Size Downloads
UQ385477_OA.pdf Full text (open access) application/pdf 4.12MB 0

Author Thoms, Julie A. I.
Knezevic, Kathy
Liu, Jia Jenny
Glaros, Elias N.
Thai, Thuan
Qiao, Qiao
Campbell, Heather
Packham, Deborah
Huang, Yizhou
Papathanasiou, Peter
Tunningley, Robert
Whittle, Belinda
Yeung, Amanda W. S.
Chandrakanthan, Vashe
Hesson, Luke
Chen, Vivien
Wong, Jason W. H.
Purton, Louise E.
Ward, Robyn L.
Thomas, Shane R.
Pimanda, John E.
Title Arrested hematopoiesis and vascular relaxation defects in mice with a mutation in Dhfr
Formatted title
Arrested hematopoiesis and vascular relaxation defects in mice with a mutation in Dhfr
Journal name Molecular and Cellular Biology   Check publisher's open access policy
ISSN 0270-7306
Publication date 2016-04
Year available 2016
Sub-type Article (original research)
DOI 10.1128/MCB.01035-15
Open Access Status File (Publisher version)
Volume 36
Issue 8
Start page 1222
End page 1236
Total pages 15
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Collection year 2017
Language eng
Formatted 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.
Keyword Dihydrofolate reductase (DHFR)
Nitric oxide (NO) signaling
Folate metabolism
Tissue-specific defects
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Office of the Vice-Chancellor
School of Medicine Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 0 times in Thomson Reuters Web of Science Article
Scopus Citation Count Cited 0 times in Scopus Article
Google Scholar Search Google Scholar
Created: Sun, 24 Apr 2016, 00:17:18 EST by System User on behalf of Learning and Research Services (UQ Library)