Neuroendocrine hormones regulate diverse physiological processes, including urination, lactation, and food intake. Many of these hormones are produced in the paraventricular and supraoptic nuclei (PVN and SON) of the hypothalamus. In the mouse, Sim1 and Sim2 are 2 transcription factors that direct the terminal differentiation of these hormone-producing PVN and SON neurons. Of particular importance, in mouse models and humans, Sim1 heterozygosity and Sim2 over-expression have been directly implicated in the pathogenesis of obesity and mental retardation, respectively. In the previous funding period, we found that 1) in Sim1 mutant mouse, hormone-expressing PVN and SON neurons are not found in their normal anatomical positions, and that 2) Sim1 heterozygous mice develop extreme obesity. Here, we propose the following aims to study these 2 outstanding issues:
Aim 1) Characterization of the neuronal migration and axonal projection defects of Sim1 mutants. The goal is to understand the structural organization of the hypothalamus and the neuronal circuitry of the PVN and SON;
Aim 2) Investigation of the molecular mechanisms underlying PVN and SON neuronal migration and axonal projection. The goal is to identify the molecules that control these 2 processes.
Aim 3) Determine if Necdin is a downstream gene of Sim1 and/or Sim2. The NECDIN (NDN) gene is implicated in causing the Prader-Willi-Syndrome (PWS), whereas the SIM1 gene is associated with a haploid-insufficient disorder similar to PWS, named PWS-Like (PWSL). The common pathology of PWS and PWSL is obesity. Our goal is to establish a regulatory relationship between Sim1 and Ndn. Through the proposed research, we hope to unravel the molecular programs controlled by Sim1 and Sim2, thereby understanding the human diseases caused by the alteration of their gene dosage.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Development - 1 Study Section (DEV)
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Henken, Deborah B
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Carnegie Institution of Washington, D.C.
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Lopez, T Peter; Fan, Chen-Ming (2013) Dynamic CREB family activity drives segmentation and posterior polarity specification in mammalian somitogenesis. Proc Natl Acad Sci U S A 110:E2019-27
Peter Lopez, T; Fan, Chen-Ming (2012) A transgenic Tbx6;CreERT2 line for inducible gene manipulation in the presomitic mesoderm. Genesis 50:490-5
Havis, Emmanuelle; Coumailleau, Pascal; Bonnet, Aline et al. (2012) Sim2 prevents entry into the myogenic program by repressing MyoD transcription during limb embryonic myogenesis. Development 139:1910-20
Osterberg, Nadja; Wiehle, Michael; Oehlke, Oliver et al. (2011) Sim1 is a novel regulator in the differentiation of mouse dorsal raphe serotonergic neurons. PLoS One 6:e19239
Xu, Cheng; Fan, Chen-Ming (2008) Expression of Robo/Slit and Semaphorin/Plexin/Neuropilin family members in the developing hypothalamic paraventricular and supraoptic nuclei. Gene Expr Patterns 8:502-7
Borillo, Jason; Coonrod, Scott A; Wu, Jean et al. (2008) Antibodies to two ZP3 B cell epitopes affect zona pellucida assembly. J Reprod Immunol 78:149-57
Friedman, Eitan R; Fan, Chen-Ming (2007) Separate necdin domains bind ARNT2 and HIF1alpha and repress transcription. Biochem Biophys Res Commun 363:113-8
Xu, Cheng; Fan, Chen-Ming (2007) Allocation of paraventricular and supraoptic neurons requires Sim1 function: a role for a Sim1 downstream gene PlexinC1. Mol Endocrinol 21:1234-45
Goshu, Eleni; Jin, Hui; Lovejoy, John et al. (2004) Sim2 contributes to neuroendocrine hormone gene expression in the anterior hypothalamus. Mol Endocrinol 18:1251-62
Liu, Chunqiao; Goshu, Eleni; Wells, Aynslee et al. (2003) Identification of the downstream targets of SIM1 and ARNT2, a pair of transcription factors essential for neuroendocrine cell differentiation. J Biol Chem 278:44857-67

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