Dihydrofolate reductase is required for the development of heart and outflow tract in zebrafish

Sun, S., Gui, Y., Jiang, Q., and Song, H.
Acta biochimica et biophysica Sinica   43(12): 957-969 (Journal)
Registered Authors
Jiang, Qiu, Song, Houyan
dihydrofolate reductase gene, cardiac development, gene expression, hedgehog pathway, cell proliferation, apoptosis, zebrafish
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Apoptosis/drug effects
  • Cell Proliferation/drug effects
  • Gene Expression Regulation, Developmental/genetics
  • Gene Knockdown Techniques
  • Heart/drug effects
  • Heart/embryology*
  • Heart/growth & development*
  • Heart Defects, Congenital/metabolism
  • Microinjections
  • Molecular Sequence Data
  • Muscle Proteins/drug effects
  • Muscle Proteins/metabolism
  • T-Box Domain Proteins/drug effects
  • T-Box Domain Proteins/metabolism
  • Tetrahydrofolate Dehydrogenase/administration & dosage
  • Tetrahydrofolate Dehydrogenase/genetics*
  • Tetrahydrofolate Dehydrogenase/metabolism*
  • Transcription Factors/drug effects
  • Transcription Factors/metabolism*
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Zebrafish Proteins/drug effects
  • Zebrafish Proteins/metabolism
22113051 Full text @ Acta. Biochim. Biophys. Sin (Shanghai)

Folic acid is very important for embryonic development and folic acid inhibition can cause congenital heart defects in vertebrates. Dihydrofolate reductase (DHFR) is a key enzyme in folate-mediated metabolism. The dysfunction of DHFR disrupts the key biological processes which folic acid participates in. DHFR gene is conserved during vertebrate evolution. It is important to investigate the roles of DHFR in cardiac developments. In this study, we showed that DHFR knockdown resulted in the abnormal developments of zebrafish embryos in the early stages. Obvious malformations in heart and outflow tract (OFT) were also observed in DHFR knockdown embryos. DHFR overexpression rescued the abnormal phenotypes in the DHFR knockdown group. DHFR knockdown had negative impacts on the expressions of NKX2.5 (NK2 transcription factor-related 5), MEF2C (myocyte-specific enhancer factor 2C), TBX20 (T-box 20), and TBX1 (T-box 1) which are important transcriptional factors during cardiac development process, while DHFR overexpression had positive effects. DHFR was required for Hedgehog pathway. DHFR knockdown caused reduced cell proliferation and increased apoptosis, while its overexpression promoted cell proliferation and inhibited apoptosis. Taken together, our study suggested that DHFR plays crucial roles in the development of heart and OFT in zebrafish by regulating gene transcriptions and affecting cell proliferation and apoptosis.

Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes