| 1998 |
SIM1 (bHLH-PAS transcription factor) is required for the terminal differentiation of at least five types of secretory neurons (oxytocin, vasopressin, TRH, CRH, somatostatin) in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. Sim1 null mice lack these neurons and die perinatally. Epistasis experiments showed SIM1 functions upstream to maintain Brn2 (POU transcription factor) expression, which in turn directs terminal differentiation of specific neuroendocrine lineages. |
Gene targeting (null allele), histological analysis, in vivo epistasis (Sim1 mutant lacks Brn2 expression in prospective PVN/SON), loss-of-function phenotypic analysis |
Genes & development |
High |
9784500
|
| 2000 |
ARNT2 acts as the dimerization partner of SIM1 for hypothalamic development. SIM1 and ARNT2 form heterodimers in vitro, are co-expressed in the PVN and SON, and loss of function of either affects the same sets of neuroendocrine cell types within the PVN and SON. |
In vitro dimerization assay, co-expression analysis, genetic loss-of-function (parallel phenotype analysis of Sim1 and Arnt2 mutants) |
Mechanisms of development |
High |
10640708
|
| 2002 |
SIM1 (and SIM2), complexed with ARNT, can bind hypoxia response elements (HRE) on the erythropoietin (EPO) enhancer. SIM1/ARNT activates transcription from the EPO enhancer at normoxia, while SIM2/ARNT represses it. Both SIM factors attenuate hypoxia-inducible transcription from the EPO enhancer. SIM proteins compete with HIF for ARNT and can repress AHR (dioxin receptor)-induced transcription from a xenobiotic response element reporter, indicating cross-talk through competition for ARNT. |
Stable cell lines expressing SIM1 or SIM2, reporter gene assays (HRE-luciferase), co-immunoprecipitation of EPO enhancer sequences with SIM2, competition assays with HIF and AHR |
The Journal of biological chemistry |
High |
11782478
|
| 2001 |
Sim1 haploinsufficiency in mice causes hyperphagic obesity with increased linear growth, hyperinsulinemia, and hyperleptinemia, without decreased energy expenditure. The PVN of Sim1+/- mice contains ~24% fewer cells. The hyperphagic phenotype without reduced energy expenditure distinguishes Sim1 deficiency from leptin and Mc4r deficiency models, suggesting PVN hypodevelopment is the causal mechanism. |
Heterozygous Sim1 knockout mice, quantitative histology of PVN, metabolic phenotyping (food intake, energy expenditure, hormones) |
Human molecular genetics |
High |
11448938
|
| 2003 |
SIM1/ARNT2 heterodimers function as transcriptional activators to control neuroendocrine differentiation in the hypothalamus. Microarray screening of inducible SIM1/ARNT2 expression in a neuronal cell line identified 268 potential downstream target genes (>1.7-fold induced). Jak2 and thyroid hormone receptor beta2 (TRbeta2) expression was confirmed as lost in the neuroendocrine hypothalamus of Sim1 mutant mice, establishing them as in vivo downstream targets. |
Inducible gene expression system in neuronal cell line, microarray analysis, Northern blot confirmation, in vivo validation in Sim1 mutant mice |
The Journal of biological chemistry |
High |
12947113
|
| 2003 |
Arylhydrocarbon receptor (AHR)-ARNT/ARNT2 complexes positively regulate the Sim1 promoter. A consensus AHR-ARNT/2 binding site in the Sim1 promoter is required for activation; its mutation abolishes AHR-ARNT/2-mediated induction. TCDD (an AHR ligand) increases Sim1 expression in Neuro-2A cells and in mouse hypothalamus, demonstrating that AHR-ARNT pathway drives Sim1 transcription. |
Promoter characterization, gel shift assay (EMSA), transfection reporter assays in Neuro-2A cells with site-directed mutagenesis, TCDD treatment and qPCR in vivo |
The Journal of biological chemistry |
High |
14660629
|
| 2004 |
A novel nuclear localization signal (NLS) was identified in human SIM1 (21 amino acids at the central part of the protein). EGFP-fusion protein assays demonstrated nuclear localization of SIM1. The NLS contains a cluster of basic amino acids with Pro and Tyr at the C-terminal end, and the consensus sequence RKxxKx[K/R]xxxxKxKxRxxPY is conserved across species. |
EGFP-fusion protein transfection assays, deletion and amino acid substitution constructs to map NLS, fluorescence microscopy |
Biochemical and biophysical research communications |
Medium |
14697214
|
| 2006 |
Sim1 heterozygous mice are resistant to hypothalamic melanocortin signaling: they fail to activate PVN neurons (c-Fos expression) in response to the melanocortin agonist MTII at doses that suppress feeding in wild-type mice, despite having normal PVN neuron numbers. The blunted feeding suppression is not due to reduced energy expenditure, and is not attributable to reduced Sim1 neuron numbers in PVN. Hypothalamic Sim1 expression is induced by leptin and MTII. |
Pharmacological challenge with melanocortin agonist MTII in Sim1+/- mice, c-Fos immunostaining of PVN neurons, food intake measurements, gene expression analysis |
Molecular endocrinology (Baltimore, Md.) |
High |
16728530
|
| 2006 |
SIM1 overexpression in transgenic mice completely rescues the hyperphagia of agouti yellow mice (in which melanocortin signaling is abrogated by ectopic expression of the agouti protein blocking MC4R) and confers resistance to diet-induced obesity through reduced food intake without change in energy expenditure. This establishes that MC4R signals through Sim1 or its transcriptional targets to control food intake. |
Transgenic overexpression of human SIM1, breeding to agouti yellow background, food intake and energy expenditure measurements |
Endocrinology |
High |
16709610
|
| 2006 |
Postnatal (adenoviral) modulation of Sim1 expression in the PVN of wild-type mice directly controls food intake: shRNA-mediated knockdown of Sim1 in PVN increased food intake by ~22%, while adenoviral overexpression of Sim1 in PVN decreased food intake by ~20%. |
Adenoviral vector-mediated shRNA knockdown and overexpression of Sim1 by stereotaxic injection into the PVN, food intake measurement |
The Journal of neuroscience |
High |
16807340
|
| 2007 |
SIM1 is required for proper neuronal migration of PVN/SON cells. Contrary to earlier proposals, SIM1 mutant cells are generated normally and survive to birth, but fail to migrate to the correct position, instead occupying an ectopic region between PVN and SON. SIM1 transcriptionally regulates neuronal migration cues: PlexinA1 is upregulated and PlexinC1 is downregulated in Sim1 mutant cells. PlexinC1 mutant mice show a selective defect in partitioning VP and OT neurons into PVN and SON. |
Tau-LacZ knock-in allele for cell tracing, immunohistochemistry, in vivo gene expression analysis in Sim1 mutants, PlexinC1 mutant mouse analysis |
Molecular endocrinology (Baltimore, Md.) |
High |
17356169
|
| 2008 |
Reduced oxytocin (Oxt) neuropeptide expression mediates the hyperphagic obesity of Sim1+/- mice. Oxt mRNA and peptide are decreased by ~80% in Sim1+/- mice. Sim1+/- mice are hypersensitive to the orexigenic effect of an Oxt receptor antagonist. Central Oxt administration reduces food intake and weight gain in Sim1+/- mice at doses that do not affect wild-type mice. Mc4r agonist activates PVN Oxt neurons in wild-type mice, placing Oxt downstream of melanocortin signaling in Sim1 neurons. |
qPCR and peptide measurement of neuropeptides in hypothalamus, central pharmacological administration of Oxt receptor antagonist and Oxt, food intake measurement, c-Fos activation of Oxt neurons by Mc4r agonist |
Molecular endocrinology (Baltimore, Md.) |
High |
18451093
|
| 2009 |
Olig2 regulates the expression of Sim1 in diencephalic progenitors, acting upstream in a pathway specifying dopaminergic neurons. Gain-of-function of Sim1 rescues the dopaminergic neuron deficits caused by Olig2 knockdown in zebrafish, establishing Sim1 as a downstream effector of Olig2 in basal diencephalic DA neuron commitment. |
Loss-of-function (morpholino knockdown) and gain-of-function of Olig2 and Sim1 in zebrafish, DA neuron quantification, genetic epistasis via rescue experiment |
Developmental dynamics |
Medium |
19253397
|
| 2010 |
Postnatal CNS deletion of Sim1 (conditional knockout using CaMKII-Cre) causes hyperphagic obesity phenocopying germline Sim1 heterozygotes, demonstrating that Sim1 has postdevelopmental physiological functions in energy balance beyond hypothalamic formation. Conditional Sim1 homozygotes reveal dosage-dependent effects on obesity without global PVN hypocellularity. Conditional knockouts exhibit decreased hypothalamic Oxt and PVN Mc4r mRNA, placing Sim1 upstream of the leptin-melanocortin-oxytocin pathway. |
Conditional Cre-lox deletion (CaMKII-Cre), stereological cell counting, retrograde tract tracing, gene expression analysis |
The Journal of neuroscience |
High |
20220015
|
| 2011 |
Sim1 is a regulator of dorsal raphe serotonergic (5-HT) neuron differentiation. Sim1-/- mice show a selective reduction in dorsal raphe nucleus 5-HT neurons. Sim1 acts upstream of the transcription factors Pet1 and Tph2, and also regulates Lhx8 and Rgs4 in serotonergic neurons. This was confirmed by in vitro gain- and loss-of-function approaches. |
Sim1-/- mouse analysis, neuron counting, gene expression analysis, in vitro gain- and loss-of-function experiments |
PloS one |
Medium |
21541283
|
| 2012 |
Ablation of Sim1-expressing neurons in adult mice causes obesity via both hyperphagia and reduced energy expenditure (including reduced thermogenesis, decreased UCP1, and decreased body temperature). This differs from Sim1 haploinsufficiency which does not reduce energy expenditure, suggesting that complete loss of Sim1 neurons additionally impairs thermogenesis via the PVH. Hypothalamic Oxt and TRH expression were reduced ~50% following neuron ablation. |
Cre/iDTR system with intracerebroventricular diphtheria toxin injection for Sim1 neuron ablation, metabolic cage analysis (food intake, energy expenditure, body temperature, BAT temperature, UCP1 expression), gene expression |
PloS one |
High |
22558467
|
| 2013 |
Thirteen heterozygous SIM1 variants in severely obese patients were identified; 9/13 significantly reduced the ability of SIM1 to activate a SIM1-responsive reporter gene in stable cell lines co-expressing ARNT or ARNT2. Loss-of-function SIM1 variants co-segregate with obesity and are associated with increased food intake, normal basal metabolic rate, autonomic dysfunction, and neurobehavioral phenotype. The phenotypic similarities with MC4R deficiency implicate altered melanocortin signaling. |
SIM1 coding region sequencing, stable cell line reporter assay with ARNT/ARNT2 co-expression, family co-segregation analysis, clinical phenotyping |
The Journal of clinical investigation |
High |
23778139
|
| 2013 |
Rare SIM1 variants (p.T46R, p.H323Y, p.T714A) show strong loss-of-function effects on SIM1 transcriptional activity in stable cell lines using luciferase reporter assays and are associated with high intra-family risk for obesity, confirming a firm link between SIM1 loss of function and severe obesity with or without Prader-Willi-like features. |
SIM1 sequencing, stable cell line luciferase reporter assays, family co-segregation analysis |
The Journal of clinical investigation |
High |
23778136
|
| 2013 |
MC4R expression selectively restored in Sim1 neurons (in Mc4r-null background) dramatically reduces obesity; the anti-obesity effect is completely reversed by selective disruption of glutamate (VGLUT2-dependent) release from those same Sim1 neurons. This establishes glutamate as the primary neurotransmitter mediating MC4R function in Sim1 neurons for body weight regulation, acting on both food intake and energy expenditure. |
Conditional MC4R restoration in Sim1 neurons (Cre-dependent), conditional disruption of glutamate release (VGLUT2 knockout in Sim1 neurons), metabolic phenotyping |
Cell metabolism |
High |
24315371
|
| 2014 |
Tamoxifen-inducible neuronal inactivation of Sim1 in adult mice with mature hypothalamic circuitry causes increased food and water intake and decreased expression of PVN neuropeptides (especially oxytocin and vasopressin), without change in energy expenditure and without loss of PVN neurons. This directly demonstrates Sim1 acts physiologically (not only developmentally) to regulate body weight and neuropeptide expression. |
Tamoxifen-inducible neural-specific Cre transgene for conditional Sim1 inactivation in adults, food/water intake measurement, neuropeptide gene expression, PVN neuron counting |
Endocrinology |
High |
24773343
|
| 2014 |
Low-activity human SIM1 variants associated with obesity frequently have impaired dimerization with the essential partner protein ARNT2. Equivalent variants in the related SIM2 produce near-identical dimerization defects. Homology modeling of the PAS domains identified a mutational 'hot-spot' in SIM1 critical for the SIM1-ARNT2 dimerization interface, with variants V290E and V326F predicted and confirmed to be low-activity. |
In vitro reporter assays for SIM1 activity in stable cell lines, dimerization assays, homology modeling of PAS domains, site-directed mutagenesis |
The Biochemical journal |
High |
24814368
|
| 2014 |
Dnmt3a in Sim1-expressing neurons in the PVH is required for normal energy homeostasis. Deletion of Dnmt3a in Sim1 neurons causes obesity, hyperphagia, decreased energy expenditure, and glucose intolerance. Tyrosine hydroxylase (TH) and galanin are upregulated targets in the PVH upon Dnmt3a deletion, and the TH promoter shows decreased DNA methylation, establishing Dnmt3a-mediated epigenetic regulation of specific gene targets in Sim1 neurons. |
Conditional Cre-lox deletion of Dnmt3a in Sim1 neurons, metabolic phenotyping, gene expression profiling, DNA methylation analysis of TH promoter |
The Journal of neuroscience |
Medium |
25392496
|
| 2015 |
Sim1 is required for proper migration of V3 spinal interneurons and guidance of their commissural (contralateral) axon projections in the developing mouse spinal cord. In Sim1 mutants, V3 INs are produced normally but fail to form proper dorso-ventral subgroups (dorsal subgroup reduced, intermediate subgroup increased). Retrograde labeling showed reduced contralateral axon projections without affecting ipsilateral projections. |
Sim1-Cre fate tracing with tdTomato reporter in Sim1 mutant background, retrograde tract labeling, temporal analysis of V3 IN positioning |
Developmental neurobiology |
Medium |
25652362
|
| 2015 |
Sim1 inhibits bone formation by stimulating the sympathetic nervous system. Adult-onset Sim1 deletion in mice increases bone formation and bone mass, while Sim1-overexpressing transgenic mice show decreased bone formation. Sim1 does not directly regulate osteoblastogenesis (bone marrow mesenchymal stem cells from Sim1 mutants differentiate normally in vitro). Sympathetic tone is decreased by Sim1 deletion and increased by Sim1 overexpression; β-adrenergic agonist (isoproterenol) reverses high bone mass in Sim1-knockout mice. |
Adult-onset Sim1 deletion (conditional KO), Sim1-overexpressing transgenic mice, bone histomorphometry, osteoblast differentiation assay, sympathetic tone measurement, isoproterenol treatment rescue |
Endocrinology |
High |
25607894
|
| 2017 |
GLP-1 receptor (Glp1r) signaling in Sim1-expressing neurons is required for physiological and behavioral stress responses. Knockdown of Glp1r in Sim1 neurons reduces HPA axis responses to both acute and chronic stress, attenuates stress-induced cardiovascular responses with decreased sympathetic drive to the heart, and reduces anxiety-like behavior. This establishes a brainstem GLP-1 → PVN Sim1 neuron circuit for coordinating neuroendocrine, autonomic, and behavioral stress responses. |
Cre-lox conditional Glp1r knockdown in Sim1 neurons, HPA axis measurement (ACTH, corticosterone), cardiovascular monitoring, behavioral tests (anxiety) |
The Journal of neuroscience |
High |
28053040
|
| 2018 |
MC4R signaling in Sim1-expressing neurons is sufficient for normal male sexual function. Mice expressing MC4R exclusively on Sim1 neurons (tbMC4RSim1 mice) on an Mc4r-null background showed reversal of sexual deficits (mounting latency, intromission efficiency, ejaculation) seen in MC4R-null mice. MC4R reexpression was found in medial amygdala and PVN. |
Conditional MC4R restoration exclusively in Sim1 neurons in Mc4r-null background (Cre-dependent), sexual behavior scoring |
Endocrinology |
Medium |
29059347
|
| 2019 |
LepRb signaling in Sim1-expressing neurons regulates body temperature and adaptive thermogenesis. Sim1-specific deletion of LepRb causes decreased surface and core body temperatures, decreased energy expenditure at ambient temperature, and disrupted cold-induced nonshivering thermogenesis (defective UCP1 upregulation in BAT and reduced serum T4). Paradoxically, Sim1-LepRb-deficient mice are hypophagic on regular chow but gain more weight on high-fat diet. |
LepRb-floxed × Sim1-Cre conditional knockout, core and surface body temperature measurement, metabolic cage analysis, BAT UCP1 expression, thyroid hormone measurement |
Endocrinology |
Medium |
30802281
|
| 2021 |
Irx3 and Irx5 are ectopically expressed in Sim1+ PVH neurons of Sim1+/- mice. Reducing the dosage of Irx3 and Irx5 or PVH-specific deletion of Irx3 ameliorates the defects of Sim1+/- mice, demonstrating that misexpression of Irx3 and Irx5 is a central molecular mechanism by which Sim1 haploinsufficiency disrupts PVH development and feeding regulation. Single-cell RNA sequencing identified two major populations of Sim1+ PVH neurons differentially affected by Sim1 haploinsufficiency. |
Single-cell RNA sequencing, genetic dosage reduction of Irx3/Irx5, PVH-specific Irx3 deletion by Cre-lox, behavioral phenotype rescue |
Science advances |
High |
34705510
|
| 2024 |
GH receptor (GHR) signaling in Sim1-expressing neurons (a subset of VGLUT2 glutamatergic neurons) is required for normal glycemia and hepatic insulin sensitivity. Sim1-specific GHR ablation causes reduced glycemia, improved glucose tolerance and insulin sensitivity, and reduced endogenous glucose production (improved hepatic insulin sensitivity) without affecting whole-body or muscle glucose uptake. Pharmacological activation of ATP-sensitive potassium channels in the brain normalizes blood glucose in Sim1-ΔGHR mice, implicating central glucose sensing. |
Conditional GHR knockout in Sim1 neurons (Cre-lox), glucose tolerance tests, insulin sensitivity tests, hyperinsulinemic-euglycemic clamp, pharmacological intervention with KATP channel activator |
Proceedings of the National Academy of Sciences of the United States of America |
High |
39700135
|
| 2005 |
SIM1 and SIM2 are co-expressed in the developing mammillary body (MB) and are jointly required for proper axonal targeting of MB neurons. In Sim1/Sim2 double mutants, MB neurons are generated and survive, but the mammillothalamic (MTT) and mammillotegmental (MTEG) tracts are absent. Sim1 alone contributes to MB axon development. SIM1/SIM2 regulate Rig-1/Robo3 expression (a negative regulator of Slit signaling) in MB, potentially mediating midline avoidance of MB axons. |
Sim1 and Sim2 single and compound mutant mice, tau-lacZ axon tracing, in situ hybridization for Slit/Robo genes, histological analysis |
Development (Cambridge, England) |
Medium |
16291793
|