Vertebrate heart growth is regulated by functional antagonism between Gridlock and Gata5.
Embryonic organs attain their final dimensions through the generation of proper cell number and size, but the control mechanisms remain obscure. Here, we establish Gridlock (Grl), a Hairy-related basic helix-loop-helix (bHLH) transcription factor, as a negative regulator of cardiomyocyte proliferative growth in zebrafish embryos. Mutations in grl cause an increase in expression of a group of immediate-early growth genes, myocardial genes, and development of hyperplastic hearts. Conversely, cardiomyocytes with augmented Grl activity have diminished cell volume and fail to divide, resulting in a marked reduction in heart size. Both bHLH domain and carboxyl region are required for Grl negative control of myocardial proliferative growth. These Grl-induced cardiac effects are counterbalanced by the transcriptional activator Gata5 but not Gata4, which promotes cardiomyocyte expansion in the embryo. Biochemical analyses show that Grl forms a complex with Gata5 through the carboxyl region and can repress Gata5-mediated transcription via the bHLH domain. Hence, our studies suggest that Grl regulates embryonic heart growth via opposing Gata5, at least in part through their protein interactions in modulating gene expression.
Jia
Haibo
H
Department of Medicine and Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
King
Isabelle N
IN
Chopra
Sameer S
SS
Wan
Haiyan
H
Ni
Terri T
TT
Jiang
Charlie
C
Guan
Xiaoqun
X
Wells
Sam
S
Srivastava
Deepak
D
Zhong
Tao P
TP
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002455:Cell Division; D047108:Embryonic Development; D050992:GATA5 Transcription Factor / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D006321:Heart / Q000033:anatomy & histology / Q000196:embryology / Q000254:growth & development*; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics*
D051792:Basic Helix-Loop-Helix Proteins; D050992:GATA5 Transcription Factor; D029961:Zebrafish Proteins; C405954:hey2 protein, zebrafish
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