| Autor: |
Maskell LJ; Medical Molecular Biology Unit, Institute of Cardiovascular Science, University College London, UCL Rayne Building, London, UK., Qamar K; Medical Molecular Biology Unit, Institute of Cardiovascular Science, University College London, UCL Rayne Building, London, UK., Babakr AA; Medical Molecular Biology Unit, Institute of Cardiovascular Science, University College London, UCL Rayne Building, London, UK., Hawkins TA; Division of Biosciences, Cell and Developmental Biology, UCL, London, UK., Heads RJ; Cardiovascular Division, Faculty of Life Sciences and Medicine, King's College London, London, UK., Budhram-Mahadeo VS; Medical Molecular Biology Unit, Institute of Cardiovascular Science, University College London, UCL Rayne Building, London, UK. |
| Abstrakt: |
Congenital heart defects contribute to embryonic or neonatal lethality but due to the complexity of cardiac development, the molecular changes associated with such defects are not fully understood. Here, we report that transcription factors (TFs) Brn-3a (POU4F1) and Brn-3b (POU4F2) are important for normal cardiac development. Brn-3a directly represses Brn-3b promoter in cardiomyocytes and consequently Brn-3a knockout (KO) mutant hearts express increased Brn-3b mRNA during mid-gestation, which is linked to hyperplastic growth associated with elevated cyclin D1, a known Brn-3b target gene. However, during late gestation, Brn-3b can cooperate with p53 to enhance transcription of pro-apoptotic genes e.g. Bax, thereby increasing apoptosis and contribute to morphological defects such as non-compaction, ventricular wall/septal thinning and increased crypts/fissures, which may cause lethality of Brn-3a KO mutants soon after birth. Despite this, early embryonic lethality in e9.5 double KO (Brn-3a -/- : Brn-3b -/- ) mutants indicate essential functions with partial redundancy during early embryogenesis. High conservation between mammals and zebrafish (ZF) Brn-3b (87%) or Brn-3a (76%) facilitated use of ZF embryos to study potential roles in developing heart. Double morphant embryos targeted with morpholino oligonucleotides to both TFs develop significant cardiac defects (looping abnormalities and valve defects) suggesting essential roles for Brn-3a and Brn-3b in developing hearts. |
