Temporal regulation of a paired-like homeodomain repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis.
Understanding the functional significance of the coordinate expression of specific corepressors and DNA-binding transcription factors remains a critical question in mammalian development. During the development of the pituitary gland, two highly related paired-like homeodomain factors, a repressor, Hesx1/Rpx and an activator, Prop-1, are expressed in sequential, overlapping temporal patterns. Here we show that while the repressive actions of Hesx1/Rpx may be required for initial pituitary organ commitment, progression beyond the appearance of the first pituitary (POMC) lineage requires both loss of Hesx1 expression and the actions of Prop-1. Although Hesx1 recruits both the Groucho-related corepressor TLE1 and the N-CoR/Sin3/HDAC complex on distinct domains, the repressor functions of Hesx1 in vivo prove to require the specific recruitment of TLE1, which exhibits a spatial and temporal pattern of coexpression during pituitary organogenesis. Furthermore, Hesx1-mediated repression coordinates a negative feedback loop with FGF8/FGF10 signaling in the ventral diencephalon, required to prevent induction of multiple pituitary glands from oral ectoderm. Our data suggest that the opposing actions of two structurally-related DNA-binding paired-like homeodomain transcription factors, binding to similar cognate elements, coordinate pituitary organogenesis by reciprocally repressing and activating target genes in a temporally specific fashion, on the basis of the actions of a critical, coexpressed TLE corepressor.
Dasen
J S
JS
Howard Hughes Medical Institute, School and Department of Medicine, University of California San Diego, La Jolla, California 92093, USA.
Martinez Barbera
J P
JP
Herman
T S
TS
Connell
S O
SO
Olson
L
L
Ju
B
B
Tollkuhn
J
J
Baek
S H
SH
Rose
D W
DW
Rosenfeld
M G
MG
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D015153:Blotting, Western; D019070:Cell Lineage; D056970:Co-Repressor Proteins; D005314:Embryonic and Fetal Development / Q000235:genetics*; D019143:Evolution, Molecular; D025461:Feedback, Physiological; D005346:Fibroblast Growth Factors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D046911:Macromolecular Substances; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010902:Pituitary Gland / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D056970:Co-Repressor Proteins; D005346:Fibroblast Growth Factors; D018398:Homeodomain Proteins; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D000072056:Transcription Factor HES-1; C489736:HESX1 protein, human; C489734:Hes1 protein, mouse; C489733:Hesx1 protein, mouse; C102134:Prophet of Pit-1 protein; C499043:TLE1 protein, human; C434946:Tle1 protein, mouse; C078493:HES1 protein, human