title: Deletion of the Ttf1 gene in differentiated neurons disrupts female reproduction without impairing basal ganglia function.
abstract: Thyroid transcription factor 1 (TTF1) [also known as Nkx2.1 (related to the NK-2 class of homeobox genes) and T/ebp (thyroid-specific enhancer-binding protein)], a homeodomain gene required for basal forebrain morphogenesis, remains expressed in the hypothalamus after birth, suggesting a role in neuroendocrine function. Here, we show an involvement of TTF1 in the control of mammalian puberty and adult reproductive function. Gene expression profiling of the nonhuman primate hypothalamus revealed that TTF1 expression increases at puberty. Mice in which the Ttf1 gene was ablated from differentiated neurons grew normally and had normal basal ganglia/hypothalamic morphology but exhibited delayed puberty, reduced reproductive capacity, and a short reproductive span. These defects were associated with reduced hypothalamic expression of genes required for sexual development and deregulation of a gene involved in restraining puberty. No extrapyramidal impairments associated with basal ganglia dysfunction were apparent. Thus, although TTF1 appears to fulfill only a morphogenic function in the ventral telencephalon, once this function is satisfied in the hypothalamus, TTF1 remains active as part of the transcriptional machinery controlling female sexual development.
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center/Oregon Health & Science University, Beaverton, Oregon 97006, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Mastronardi
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Smiley
authors.forename: Jacob
authors.initials: J
authors.lastname: Raber
authors.forename: Takashi
authors.initials: T
authors.lastname: Kusakabe
authors.forename: Akio
authors.initials: A
authors.lastname: Kawaguchi
authors.forename: Valerie
authors.initials: V
authors.lastname: Matagne
authors.forename: Anja
authors.initials: A
authors.lastname: Dietzel
authors.forename: Sabine
authors.initials: S
authors.lastname: Heger
authors.forename: Alison E
authors.initials: AE
authors.lastname: Mungenast
authors.forename: Ricardo
authors.initials: R
authors.lastname: Cabrera
authors.forename: Shioko
authors.initials: S
authors.lastname: Kimura
authors.forename: Sergio R
authors.initials: SR
authors.lastname: Ojeda
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000166:cytology / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000502:physiology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics*; D012098:Reproduction / Q000235:genetics*; D012726:Sexual Behavior, Animal / Q000502:physiology; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics*
chemical_list: C000614412:NKX2-1 protein, human; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors