Zebrafish early cardiac connexin, Cx36.7/Ecx, regulates myofibril orientation and heart morphogenesis by establishing Nkx2.5 expression

Sultana, N., Nag, K., Hoshijima, K., Laird, D.W., Kawakami, A., and Hirose, S.
Proceedings of the National Academy of Sciences of the United States of America   105(12): 4763-4768 (Journal)
Registered Authors
Hoshijima, Kazuyuki, Kawakami, Atsushi
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Connexins/chemistry
  • Connexins/metabolism*
  • Down-Regulation/genetics
  • Embryo, Nonmammalian/abnormalities
  • Embryo, Nonmammalian/ultrastructure
  • Gene Expression Regulation, Developmental
  • HeLa Cells
  • Heart/embryology*
  • Heart Defects, Congenital/genetics
  • Humans
  • Molecular Sequence Data
  • Morphogenesis*
  • Mutation/genetics
  • Myocardium/pathology
  • Myocardium/ultrastructure
  • Myofibrils/metabolism*
  • Myofibrils/pathology
  • Myofibrils/ultrastructure
  • Phenotype
  • Transcription Factors/chemistry
  • Transcription Factors/metabolism*
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
18337497 Full text @ Proc. Natl. Acad. Sci. USA
Heart development is a precisely coordinated process of cellular proliferation, migration, differentiation, and integrated morphogenetic interactions, and therefore it is highly susceptible to developmental anomalies such as the congenital heart disease (CHD). One of the major causes of CHD has been shown to be the mutations in key cardiac transcription factors, including nkx2.5. Here, we report the analysis of zebrafish mutant ftk that showed a progressive heart malformation in the later stages of heart morphogenesis. Our analyses revealed that the cardiac muscle maturation and heart morphogenesis in ftk mutants were impaired because of the disorganization of myofibrils. Notably, we found that the expression of nkx2.5 was down-regulated in the ftk heart despite the normal expression of gata4 and tbx5, suggesting a common mechanism for togenesis in ftk mutants were impaired because of the disorganization of myofibrils. Notably, we found that the expression of nkx2.5 was down-regulahe occurrence of ftk phenotype and CHD. We identified ftk to be a loss-of-function mutation in a connexin gene, cx36.7/early cardiac connexin (ecx), expressed during early heart development. We further showed by a rescue experiment that Nkx2.5 is the downstream mediator of Ecx-mediated signaling. From these results, we propose that the cardiac connexin Ecx and its downstream signaling are crucial for establishing nkx2.5 expression, which in turn promotes unidirectional, parallel alignment of myofibrils and the subsequent proper heart morphogenesis.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes