Cardiac expression of Brn-3a and Brn-3b POU transcription factors and regulation of Hsp27 gene expression.
The Brn-3 family of transcription factors play a critical role in regulating expression of genes that control cell fate, including the small heat shock protein Hsp27. The aim of this study was to investigate the relationship between Brn-3a and Brn-3b and Hsp27 expression in the developing rodent heart. Brn-3a and Brn-3b were detected from embryonic days 9.5-10.5 (E9.5-E10.5) in the mouse heart, with significant increases seen later during development. Two isoforms (long and short) of each protein were detected during embryogenesis and postnatally. Brn-3a messenger RNA (mRNA) and protein were localized by E13.0 to the atrio-ventricular (AV) valve cushions and leaflets, outflow tract (OFT), epicardium and cardiac ganglia. By E14.5, Brn-3a was also localised to the septa and compact ventricular myocardium. An increase in expression of the long Brn-3a(l) isoform between E17 and adult coincided with a decrease in expression of Brn-3b(l) and a marked increase in expression of Hsp27. Hearts from Brn-3a-/- mice displayed a partially penetrant phenotype marked by thickening of the endocardial cushions and AV valve leaflets and hypoplastic ventricular myocardium. Loss of Brn-3a was correlated with a compensatory increase in Brn-3b and GATA3 mRNA but no change in Hsp27 mRNA. Reporter assays in isolated cardiomyocytes demonstrated that both Brn-3a and Brn-3b activate the hsp27 promoter via a consensus Brn-3-binding site. Therefore, Brn-3 POU factors may play an important role in the development and maintenance of critical cell types and structures within the heart, in part via developmental regulation of myocardial Hsp27 expression. Furthermore, Brn-3a may be necessary for correct valve and myocardial remodelling and maturation.
Farooqui-Kabir
Saleha R
SR
Cardiovascular Division, King's College London School of Medicine, Department of Cardiology, The Rayne Institute, St Thomas's Hospital, Lambeth Palace Road, London, UK.
Diss
James K J
JK
Henderson
Deborah
D
Marber
Michael S
MS
Latchman
David S
DS
Budhram-Mahadeo
Vishwanie
V
Heads
Richard J
RJ
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D005838:Genotype; D055551:HSP27 Heat-Shock Proteins; D006321:Heart / Q000033:anatomy & histology / Q000196:embryology; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D050819:Transcription Factor Brn-3A / Q000235:genetics / Q000378:metabolism*; D050820:Transcription Factor Brn-3B / Q000235:genetics / Q000378:metabolism*
D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018398:Homeodomain Proteins; C486699:Hspb2 protein, mouse; C494189:Pou4f1 protein, mouse; C085559:Pou4f2 protein, mouse; D050819:Transcription Factor Brn-3A; D050820:Transcription Factor Brn-3B