Abstract
Knockout (KO) mice lacking the orphan nuclear receptor steroidogenic factor 1 (SF-1) exhibit marked structural abnormalities of the ventromedial nucleus of the hypothalamus (VMH). In this study, we sought to determine the molecular mechanisms underlying the VMH abnormalities. To trace SF-1-expressing neurons, we used a SF-1/enhanced green fluorescent protein (eGFP) transgene. Although the total numbers of eGFP-positive cells in wild-type (WT) and SF-1 KO mice were indistinguishable, cells that normally localize precisely within the VMH were scattered more diffusely in adjacent regions in SF-1 KO mice. This abnormal distribution is likely due to the loss of SF-1 expression in VMH neurons rather than secondary effects of deficient steroidogenesis, as redistribution also was seen in mice with a CNS-specific KO of SF-1. Thus, the absence of SF-1 alters the distribution of cells that normally form the VMH within the mediobasal hypothalamus. Consistent with this model, the hypothalamic expression patterns of the transcription factors islet-1 and nkx2.1 also were displaced in SF-1 KO mice. Independent of gene expression, birthdate analyses further suggested that cells with earlier birthdates were affected more severely by the loss of SF-1 than were later born cells. We conclude that the absence of SF-1 causes major changes in cellular arrangement within and around the developing VMH that result from altered cell migration.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Body Patterning / genetics
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Cell Differentiation / genetics
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Cell Division / genetics
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Cell Movement / genetics*
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / deficiency*
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DNA-Binding Proteins / genetics
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Female
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Gene Expression Regulation, Developmental / genetics*
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Gonadal Steroid Hormones / biosynthesis
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Homeodomain Proteins
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Male
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Mice
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Mice, Knockout
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Nervous System Malformations / genetics
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Nervous System Malformations / metabolism
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Nervous System Malformations / pathology*
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Neurons / metabolism
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Neurons / pathology*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Receptors, Cytoplasmic and Nuclear
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Stem Cells / cytology
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Stem Cells / metabolism
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Steroidogenic Factor 1
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Thyroid Nuclear Factor 1
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Transcription Factors / biosynthesis
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Transcription Factors / deficiency*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transgenes / genetics
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Ventromedial Hypothalamic Nucleus / abnormalities*
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Ventromedial Hypothalamic Nucleus / metabolism
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Ventromedial Hypothalamic Nucleus / pathology
Substances
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
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Gonadal Steroid Hormones
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Homeodomain Proteins
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Mapk8ip protein, mouse
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Nkx2-1 protein, mouse
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Nuclear Proteins
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Receptors, Cytoplasmic and Nuclear
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Recombinant Fusion Proteins
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Steroidogenic Factor 1
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Thyroid Nuclear Factor 1
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Transcription Factors
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steroidogenic factor 1, mouse