University of Oulu

Rosendahl, A.-H., Monnius, M., Laitala, A., Railo, A., Miinalainen, I., Heljasvaara, R., Mäki, J. M., & Myllyharju, J. (2022). Deletion of hypoxia-inducible factor prolyl 4-hydroxylase 2 in FoxD1-lineage mesenchymal cells leads to congenital truncal alopecia. Journal of Biological Chemistry, 298(4), 101787.

Deletion of hypoxia-inducible factor prolyl 4-hydroxylase 2 in FoxD1-lineage mesenchymal cells leads to congenital truncal alopecia

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Author: Rosendahl, Ann-Helen1,2,3; Monnius, Mia1,2,3; Laitala, Anu1,2,3;
Organizations: 1Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
2Biocenter Oulu, University of Oulu, Oulu, Finland
3Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
4Biocenter Oulu, Electron Microscope Core Facility, University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 6.1 MB)
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Language: English
Published: American Society for Biochemistry and Molecular Biology, 2022
Publish Date: 2022-09-12


Hypoxia-inducible factors (HIFs) induce numerous genes regulating oxygen homeostasis. As oxygen sensors of the cells, the HIF prolyl 4-hydroxylases (HIF-P4Hs) regulate the stability of HIFs in an oxygen-dependent manner. During hair follicle (HF) morphogenesis and cycling, the location of dermal papilla (DP) alternates between the dermis and hypodermis and results in varying oxygen levels for the DP cells. These cells are known to express hypoxia-inducible genes, but the role of the hypoxia response pathway in HF development and homeostasis has not been studied. Using conditional gene targeting and analysis of hair morphogenesis, we show here that lack of Hif-p4h-2 in Forkhead box D1 (FoxD1)-lineage mesodermal cells interferes with the normal HF development in mice. FoxD1-lineage cells were found to be mainly mesenchymal cells located in the dermis of truncal skin, including those cells composing the DP of HFs. We found that upon Hif-p4h-2 inactivation, HF development was disturbed during the first catagen leading to formation of epithelial-lined HF cysts filled by unorganized keratins, which eventually manifested as truncal alopecia. Furthermore, the depletion of Hif-p4h-2 led to HIF stabilization and dysregulation of multiple genes involved in keratin formation, HF differentiation, and HIF, transforming growth factor β (TGF-β), and Notch signaling. We hypothesize that the failure of HF cycling is likely to be mechanistically caused by disruption of the interplay of the HIF, TGF-β, and Notch pathways. In summary, we show here for the first time that HIF-P4H-2 function in FoxD1-lineage cells is essential for the normal development and homeostasis of HFs.

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Series: Journal of biological chemistry
ISSN: 0021-9258
ISSN-E: 1083-351X
ISSN-L: 0021-9258
Volume: 298
Issue: 4
Article number: 101787
DOI: 10.1016/j.jbc.2022.101787
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This study was supported by the Academy of Finland Center of Excellence 2012 to 2017 grant (grant no.: 251314) (to J. M.) and Academy Project Grant (grant no.: 296498) (to J. M.), S. Jusélius Foundation (to J. M.), Jane and Aatos Erkko Foundation (to J. M.), FibroGen, Inc (to J. M.), The Finnish Cultural Foundation (to A.-H. R.), and the Instrumentarium Science Foundation (to A.-H. R.).
Academy of Finland Grant Number: 251314
Detailed Information: 251314 (Academy of Finland Funding decision)
296498 (Academy of Finland Funding decision)
Copyright information: © 2022 THE AUTHORS. This is an open access article under the CC BY license (