Ndrg4 is required for normal myocyte proliferation during early cardiac development in zebrafish.
NDRG4 is a novel member of the NDRG family (N-myc downstream-regulated gene). The roles of NDRG4 in development have not previously been evaluated. We show that, during zebrafish embryonic development, ndrg4 is expressed exclusively in the embryonic heart, the central nervous system (CNS) and the sensory system. Ndrg4 knockdown in zebrafish embryos causes a marked reduction in proliferative myocytes and results in hypoplastic hearts. This growth defect is associated with cardiac phenotypes in morphogenesis and function, including abnormal heart looping, inefficient circulation and weak contractility. We reveal that ndrg4 is required for restricting the expression of versican and bmp4 to the developing atrioventricular canal. This constellation of ndrg4 cardiac defects phenocopies those seen in mutant hearts of heartstrings (hst), the tbx5 loss-of-function mutants in zebrafish. We further show that ndrg4 expression is significantly decreased in hearts with reduced tbx5 activities. Conversely, increased expression of tbx5 that is due to tbx20 knockdown leads to an increase in ndrg4 expression. Together, our studies reveal an essential role of ndrg4 in regulating proliferation and growth of cardiomyocytes, suggesting that ndrg4 may function downstream of tbx5 during heart development and growth.
Qu
Xianghu
X
Department of Pediatric Cardiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Jia
Haibo
H
Garrity
Deborah M
DM
Tompkins
Kevin
K
Batts
Lorene
L
Appel
Bruce
B
Zhong
Tao P
TP
Baldwin
H Scott
HS
D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D049109:Cell Proliferation; D003001:Cloning, Molecular; D006321:Heart / Q000196:embryology; D017403:In Situ Hybridization; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009841:Oligonucleotides / Q000235:genetics; D010641:Phenotype; D020825:T-Box Domain Proteins / Q000378:metabolism; D053675:Versicans / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D009124:Muscle Proteins; C530194:Ndrg4 protein, zebrafish; D009419:Nerve Tissue Proteins; D009841:Oligonucleotides; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D029961:Zebrafish Proteins; C525813:bmp4 protein, zebrafish; D053675:Versicans