Developmental dependence on NurRE and EboxNeuro for expression of pituitary proopiomelanocortin.
Cell-specific expression of the pituitary proopiomelanocortin (POMC) gene depends on the combinatorial action of a large number of DNA-binding transcription factors (TFs). These include general and cell-restricted factors, as well as factors that act as effectors of signaling pathways. We have previously defined in the distal POMC promoter a composite regulatory element that contains targets for basic helix-loop-helix TFs conferring cell specificity and for NGFI-B orphan nuclear receptors that are responsive to CRH signaling and to glucocorticoid negative feedback. These factors act on neighboring regulatory elements, the Ebox(Neuro) and NurRE, respectively. Currently, the Ebox(Neuro) is thought to be the target of NeuroD1 during fetal development, but this factor may not account for activity in the adult pituitary; it is also unknown whether the NurRE and NGFI-B-related factors are active before establishment of the hypothalamic-pituitary portal system. In order to assess the importance of these regulatory elements and their cognate TFs throughout pituitary organogenesis and in the adult, we have assessed the activity of mutant POMC promoters in transgenic mice throughout development. These experiments indicate that the Ebox(Neuro) and cognate basic helix-loop-helix factors are required throughout development and in the adult gland, beyond expression of NeuroD1. Similarly, the data reveal sustained importance of the NurRE and its cognate factors throughout pituitary development. These data contrast the sustained dependence throughout development on the same regulatory elements with the highly dynamic patterns of TF expression and the modulation of their activity in response to signaling pathways.
Lavoie
Pierre-Luc
PL
Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal 110, Montréal, Québec, Canada.
Budry
Lionel
L
Balsalobre
Aurélio
A
Drouin
Jacques
J
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010902:Pituitary Gland / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis*; D050436:Regulatory Elements, Transcriptional; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011333:Pro-Opiomelanocortin; D014157:Transcription Factors; C093970:NEUROD1 protein, human; C539882:NR4A2 protein, human; C501008:Neurod1 protein, mouse; C539883:Nr4a2 protein, mouse