ABSTRACT
The endothelin-A receptor (Ednra) is involved in several physiological, pathological, and developmental pathways. Known for its function in vasoconstriction after being activated by endothelin-1, Ednra also controls cephalic neural crest cell development and appears to play a role in several pathologies, including cancer and periodontitis. However, the mechanisms regulating Ednra expression have not been identified despite its important functions. In this study, we investigated the role progesterone plays in Ednra gene expression in vivo and in vitro. In mice, pregnancy promotes Ednra expression in the heart, kidney, lung, uterus, and placenta, and the up-regulation is mediated by progesterone. We determined that the conserved region between -5.7 and -4.2 kb upstream of the mouse Ednra gene is necessary for the progesterone response. We also found that progesterone mediates Ednra activation through progesterone receptor B activation by its recruitment to PRE6, one of the 6 progesterone response elements found in that locus. However, gene activation by means of a GATA2 site was also necessary for the progesterone response. The Gata2 transcription factor enhances the progesterone response mediated by the progesterone receptor B. Together these results indicate that progesterone regulates Ednra expression by synergizing with Gata2 activity, a previously unknown mechanism. This mechanism may have an impact on pathologies involving the endothelin signaling.
Subject(s)
GATA2 Transcription Factor/physiology , Progesterone/physiology , Receptor, Endothelin A/genetics , Animals , Base Sequence , Female , Gene Expression Regulation , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Organ Specificity , Pregnancy , Primary Cell Culture , Promoter Regions, Genetic , Receptor, Endothelin A/metabolism , Response Elements , Sequence Analysis, DNA , Up-RegulationABSTRACT
BACKGROUND: The basic helix-loop-helix (bHLH) transcription factor Twist1 fulfills an essential function in neural crest cell formation, migration, and survival and is associated with the craniosynostic Saethre-Chotzen syndrome in humans. However, its functions during mandibular development, when it may interact with other bHLH transcription factors like Hand2, are unknown because mice homozygous for the Twist1 null mutation die in early embryogenesis. To determine the role of Twist1 during mandibular development, we used the Hand2-Cre transgene to conditionally inactivate the gene in the neural crest cells populating the mandibular pharyngeal arch. RESULTS: The mutant mice exhibited a spectrum of craniofacial anomalies, including mandibular hypoplasia, altered middle ear development, and cleft palate. It appears that Twist1 is essential for the survival of the neural crest cells involved in the development of the mandibular ramal elements. Twist1 plays a role in molar development and cusp formation by participating in the reciprocal signaling needed for the formation of the enamel knot. This gene is also needed to control the ossification of the mandible, a redundant role shared with Hand2. CONCLUSION: Twist1, along with Hand2, is essential for the proximodistal patterning and development of the mandible and ossification.
