Frisk, Jun Mei Hu and Örn, Stefan and Pejler, Gunnar and Eriksson, Staffan and Wang, Liya
(2022).
Differential expression of enzymes in thymidylate biosynthesis in zebrafish at different developmental stages: implications for dtymk mutation-caused neurodegenerative disorders.
BMC Neuroscience. 23
:1
, 19
[Research article]
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Abstract
Background Deoxythymidine triphosphate (dTTP) is an essential building block of DNA, and defects in enzymes involved in dTTP synthesis cause neurodegenerative disorders. For instance, mutations in DTYMK, the gene coding for thymidylate kinase (TMPK), cause severe microcephaly in human. However, the mechanism behind this is not well-understood. Here we used the zebrafish model and studied (i) TMPK, an enzyme required for both the de novo and the salvage pathways of dTTP synthesis, and (ii) thymidine kinases (TK) of the salvage pathway in order to understand their role in neuropathology. Results Our findings reveal that maternal-stored dNTPs are only sufficient for 6 cell division cycles, and the levels of dNTPs are inversely correlated to cell cycle length during early embryogenesis. TMPK and TK activities are prominent in the cytosol of embryos, larvae and adult fish and brain contains the highest TMPK activity. During early development, TMPK activity increased gradually from 6 hpf and a profound increase was observed at 72 hpf, and TMPK activity reached its maximal level at 96 hpf, and remained at high level until 144 hpf. The expression of dtymk encoded Dtymk protein correlated to its mRNA expression and neuronal development but not to the TMPK activity detected. However, despite the high TMPK activity detected at later stages of development, the Dtymk protein was undetectable. Furthermore, the TMPK enzyme detected at later stages showed similar biochemical properties as the Dtymk enzyme but was not recognized by the Dtymk specific antibody. Conclusions Our results suggest that active dNTP synthesis in early embryogenesis is vital and that Dtymk is essential for neurodevelopment, which is supported by a recent study of dtymk knockout zebrafish with neurological disorder and lethal outcomes. Furthermore, there is a novel TMPK-like enzyme expressed at later stages of development.
Authors/Creators: | Frisk, Jun Mei Hu and Örn, Stefan and Pejler, Gunnar and Eriksson, Staffan and Wang, Liya | ||||||
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Title: | Differential expression of enzymes in thymidylate biosynthesis in zebrafish at different developmental stages: implications for dtymk mutation-caused neurodegenerative disorders | ||||||
Series Name/Journal: | BMC Neuroscience | ||||||
Year of publishing : | 2022 | ||||||
Volume: | 23 | ||||||
Number: | 1 | ||||||
Article number: | 19 | ||||||
Number of Pages: | 13 | ||||||
Publisher: | BMC | ||||||
ISSN: | 1471-2202 | ||||||
Language: | English | ||||||
Publication Type: | Research article | ||||||
Article category: | Scientific peer reviewed | ||||||
Version: | Published version | ||||||
Copyright: | Creative Commons: Attribution 4.0 | ||||||
Full Text Status: | Public | ||||||
Subjects: | (A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 301 Basic Medicine > Neurosciences | ||||||
Keywords: | Thymidylate kinase, Dtymk, Thymidine kinase, Tk, dTTP synthesis, dNTPs, Zebrafish development, Neuronal development | ||||||
URN:NBN: | urn:nbn:se:slu:epsilon-p-116644 | ||||||
Permanent URL: | http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-p-116644 | ||||||
Additional ID: |
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ID Code: | 27539 | ||||||
Faculty: | VH - Faculty of Veterinary Medicine and Animal Science | ||||||
Department: | (VH) > Dept. of Anatomy, Physiology and Biochemistry (VH) > Department of Biomedical Science and Veterinary Public Health | ||||||
Deposited By: | SLUpub Connector | ||||||
Deposited On: | 12 Apr 2022 16:25 | ||||||
Metadata Last Modified: | 12 Apr 2022 16:31 |
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