Nkx2.5 homeoprotein regulates expression of gap junction protein connexin 43 and sarcomere organization in postnatal cardiomyocytes.
Nkx2.5, an evolutionarily conserved homeodomain containing transcription factor, is one of the earliest cardiogenic markers. Although its expression continues through adulthood, its function in adult cardiomyocytes is not well understood. To examine the effect of Nkx2.5 in terminal differentiated postnatal cardiomyocytes, we generated transgenic mice expressing either wild-type Nkx2.5 (TG-wild), a putative transcriptionally active mutant (carboxyl-terminus deletion mutant: TG-DeltaC) or a DNA non-binding point mutant of Nkx2.5 (TG-I183P) under alpha-myosin heavy chain promoter. Most TG-wild and TG-DeltaC mice died before 4 months of age with heart failure associated with conduction abnormalities. Cardiomyocytes expressing wild-type Nkx2.5 or a putative transcriptionally active mutant (DeltaC) had dramatically reduced expression of connexin 43 and changed sarcomere structure. Wild-type Nkx2.5 adenovirus-infected adult cardiomyocytes demonstrated connexin 43 downregulation as early as 16 h after infection, indicating that connexin 43 downregulation is due to Nkx2.5 overexpression but not due to heart failure phenotype in vivo. These studies indicate that overexpression of Nkx2.5 in terminally differentiated cardiomyocytes dramatically alters cardiac cell structure and function.
Kasahara
Hideko
H
Department of Medicine, Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, SL201, Boston, MA 02215, USA.
Ueyama
Tomomi
T
Wakimoto
Hiroko
H
Liu
Margaret K
MK
Maguire
Colin T
CT
Converso
Kimber L
KL
Kang
Peter M
PM
Manning
Warren J
WJ
Lawitts
Joel
J
Paul
David L
DL
Berul
Charles I
CI
Izumo
Seigo
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D004562:Electrocardiography; D005260:Female; D005822:Genetic Vectors / Q000378:metabolism; D006321:Heart / Q000254:growth & development*; D006331:Heart Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure*; D010957:Plasmids / Q000235:genetics; D051381:Rats; D012518:Sarcomeres / Q000235:genetics / Q000648:ultrastructure*; D014157:Transcription Factors; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D018031:Connexin 43; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors; D029867:Xenopus Proteins