The goal of this proposal is to investigate the function of mammalian Sim1 and Sim2 genes using transgenic mouse models. Sim1 and Sim2 are homologues of the Drosophila sim (singleminded) gene. In the fly, sim plays essential roles in the development of the central nervous system. Preliminary studies of the mouse Sim genes strongly suggest evolutionarily conserved functions. The SIM proteins contain conserved sequence motif termed the PAS domain, which is hared by several environmental sensor proteins such as the Dioxin receptor, the Hypoxia Inducible Factor, the Drosophila circadian rhythm regulator Per, and the B. subtilis sporulation regulator KinA. This information strongly indicated that SIMs may also respond to specific environmental signals via their PAS domains. This proposal includes the following aims: 1) documenting the expression patterns of Sim1 and Sim2 in detail; 2) establishing mouse models lacking Sim1 and Sim2 gene function by homologous recombination and characterizing mutant phenotypes in order to assess the normal function of these genes, and 3) identifying possible small molecule ligands that modulate the function of Sim1 and Sim2. Importantly, the mouse Sim2 gene is located in the syntenic human Down syndrome critical region. Furthermore, mutant mice lacking Sim1 display neurological disorders that may relate to multiple sclerosis. Exploration and identification of possible small ligands that regulate Sim1 and Sim2 function will be the first step towards developing methods to alter their gene activities in vivo.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Henken, Deborah B
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Carnegie Institution of Washington, D.C.
United States
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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
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
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
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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