HES1 regulates 5-HT1A receptor gene transcription at a functional polymorphism: essential role in developmental expression.
Mammalian HES1 and HES5 are abundant in developing CNS and inhibit neurogenesis, while HES6 promotes neurogenesis. An early serotonergic differentiation marker, the 5-HT1A receptor, is repressed by HES5 and DEAF1 which recognize the C(-1019), but not G(-1019) allele of a human 5-HT1A promoter polymorphism associated with mood disorders. We tested whether HES1 and HES6 regulate transcriptional activity at this element. HES1 strongly repressed 5-HT1A transcription in neuronal and non-neuronal cells, while HES6 reversed HES1- and HES5-mediated repression. Mutation of a putative HES consensus site blocked HES1 and HES5, but, unlike HES5, HES1 repressed at the G(-1019) allele. To address its role in vivo, the temporal expression of 5-HT1A receptor RNA and protein was examined in HES1-/- mice, and elevated levels in E12.5 hindbrain and midbrain were observed. Thus, HES1 and HES6 oppositely regulate 5-HT1A receptor transcription and HES1 is required for its correct developmental expression.
Jacobsen
Kirsten X
KX
Ottawa Health Research Institute (Neuroscience) and Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON Canada.
Vanderluit
Jacqueline L
JL
Slack
Ruth S
RS
Albert
Paul R
PR
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011110:Polymorphism, Genetic / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D044282:Receptor, Serotonin, 5-HT1A; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse