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Gene Review

Sim1  -  single-minded homolog 1 (Drosophila)

Mus musculus

Synonyms: Single-minded homolog 1, bHLHe14, mSIM1
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Disease relevance of Sim1

  • Sim1 haploinsufficiency causes hyperphagia in mice and humans, most likely by perturbing the hypothalamus function [1].
  • Since acquired lesions in the PVN also induce increased appetite without a decrease in energy expenditure, we propose that abnormalities of PVN development cause the obesity of Sim1(+/-) mice [2].
  • In contrast, we show here that Sim1 heterozygous mice are viable but develop early-onset obesity, with increased linear growth, hyperinsulinemia and hyperleptinemia [2].
  • In contrast, injection of an adenovirus that expresses Sim1 induced a decrease in food intake that was maximal on the seventh day after the procedure, reaching 20% [3].

Psychiatry related information on Sim1


High impact information on Sim1


Biological context of Sim1

  • We have generated, by homologous recombination, a null allele of Sim1 (Sim1(tlz)) in which the tau-lacZ fusion gene was introduced, allowing the staining of MB axons [7].
  • The expression and predicted functions of many of these genes provide new insight into both the Sim1/Arnt2 action in neuroendocrine hypothalamus development and the molecular basis for the Sim1 haplo-insufficient obesity phenotype [8].
  • Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice [4].
  • Taken together, our results demonstrate that Arnt2 is an indispensable transcription factor for the development of the hypothalamus, and suggest that Arnt2 is an obligatory partner molecule of Sim1 in the developmental process of the neuroendocrinological cell lineages [9].
  • Unilateral stereotaxic injection into the PVN of an adenoviral vector producing a short hairpin RNA directed against Sim1 resulted in a significant increase in food intake, which peaked to 22% 6 d after the procedure, compared with the injection of a control virus [3].

Anatomical context of Sim1

  • Finally, we found that TCDD increased Sim1 expression in Neuro-2A cells and in mouse kidney and hypothalamus by 4-, 3-, and 2-fold, respectively [1].
  • Gain-of-function analysis in transgenic mouse embryos indicates that Olig genes specifically inhibit the establishment of Sim1-expressing V3 interneurons [10].
  • Outside the CNS, Sim1 is expressed in mesodermal and endodermal tissues, including developing somites, mesonephric duct, and foregut [11].

Other interactions of Sim1

  • Genetically, Sim1 acts upstream of Sim2 and partially compensates for the loss of Sim2 [12].
  • Here, we provide evidence that Sim1 and Arnt2 form dimers in vitro, that they are co-expressed in the PVN and SON, and that their loss of function affects the development of the same sets of neuroendocrine cell types within the PVN and SON [13].
  • Furthermore, we found that expression of two of these potential targets, the Jak2 and thyroid hormone receptor beta2 genes, was lost in the neuroendocrine hypothalamus of the Sim1 mutant [8].


  1. Regulatory interaction between arylhydrocarbon receptor and SIM1, two basic helix-loop-helix PAS proteins involved in the control of food intake. Yang, C., Boucher, F., Tremblay, A., Michaud, J.L. J. Biol. Chem. (2004) [Pubmed]
  2. Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Michaud, J.L., Boucher, F., Melnyk, A., Gauthier, F., Goshu, E., Lévy, E., Mitchell, G.A., Himms-Hagen, J., Fan, C.M. Hum. Mol. Genet. (2001) [Pubmed]
  3. Adenoviral-mediated modulation of Sim1 expression in the paraventricular nucleus affects food intake. Yang, C., Gagnon, D., Vachon, P., Tremblay, A., Levy, E., Massie, B., Michaud, J.L. J. Neurosci. (2006) [Pubmed]
  4. Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice. Holder, J.L., Zhang, L., Kublaoui, B.M., DiLeone, R.J., Oz, O.K., Bair, C.H., Lee, Y.H., Zinn, A.R. Am. J. Physiol. Endocrinol. Metab. (2004) [Pubmed]
  5. Development of neuroendocrine lineages requires the bHLH-PAS transcription factor SIM1. Michaud, J.L., Rosenquist, T., May, N.R., Fan, C.M. Genes Dev. (1998) [Pubmed]
  6. Sim2 mutants have developmental defects not overlapping with those of Sim1 mutants. Goshu, E., Jin, H., Fasnacht, R., Sepenski, M., Michaud, J.L., Fan, C.M. Mol. Cell. Biol. (2002) [Pubmed]
  7. Sim1 and Sim2 are required for the correct targeting of mammillary body axons. Marion, J.F., Yang, C., Caqueret, A., Boucher, F., Michaud, J.L. Development (2005) [Pubmed]
  8. Identification of the downstream targets of SIM1 and ARNT2, a pair of transcription factors essential for neuroendocrine cell differentiation. Liu, C., Goshu, E., Wells, A., Fan, C.M. J. Biol. Chem. (2003) [Pubmed]
  9. Defective development of secretory neurones in the hypothalamus of Arnt2-knockout mice. Hosoya, T., Oda, Y., Takahashi, S., Morita, M., Kawauchi, S., Ema, M., Yamamoto, M., Fujii-Kuriyama, Y. Genes Cells (2001) [Pubmed]
  10. Olig bHLH proteins interact with homeodomain proteins to regulate cell fate acquisition in progenitors of the ventral neural tube. Sun, T., Echelard, Y., Lu, R., Yuk, D.I., Kaing, S., Stiles, C.D., Rowitch, D.H. Curr. Biol. (2001) [Pubmed]
  11. Expression patterns of two murine homologs of Drosophila single-minded suggest possible roles in embryonic patterning and in the pathogenesis of Down syndrome. Fan, C.M., Kuwana, E., Bulfone, A., Fletcher, C.F., Copeland, N.G., Jenkins, N.A., Crews, S., Martinez, S., Puelles, L., Rubenstein, J.L., Tessier-Lavigne, M. Mol. Cell. Neurosci. (1996) [Pubmed]
  12. Sim2 contributes to neuroendocrine hormone gene expression in the anterior hypothalamus. Goshu, E., Jin, H., Lovejoy, J., Marion, J.F., Michaud, J.L., Fan, C.M. Mol. Endocrinol. (2004) [Pubmed]
  13. ARNT2 acts as the dimerization partner of SIM1 for the development of the hypothalamus. Michaud, J.L., DeRossi, C., May, N.R., Holdener, B.C., Fan, C.M. Mech. Dev. (2000) [Pubmed]
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