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FLASH GENE

Symbol

SIM1

contributors: mct - updated : 10-10-2018

HGNC name	single-minded homolog 1 (Drosophila)
HGNC id	10882

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_005068 11 - 3995 NP_005059 85.4 766 - PMID: 9199934

EXPRESSION

Type

constitutive of

expressed in	(based on citations)
organ(s)

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Nervous central

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal, pregnancy

Text	in developing kidney, pancreas

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	basic helix-loop-helix (bHLH)
	a stretch of approximately 300AA, termed the PAS (period - ARNT - Sim) region
	NLS consisting of a cluster of basic amino acids with Pro and Tyr at the C-terminal

HOMOLOGY

interspecies	homolog to Drosophila (single minded 1) Sim1
	ortholog to murine Sim1

Homologene

FAMILY

BHLH/PAS transcription factor family

CATEGORY

transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus

basic FUNCTION	master regulator of fruit fly midline neurogenesis
	required for the development of all neurons of the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus
	playing an essential role for formation of the supraoptic and paraventricular(PVN) nuclei of the hypothalamus, PVN implicated in the regulation of body weight
	role in feeding regulation not limited to formation of the paraventricular nuclei
	ARNT2 and SIM1 are required to determine the lateral position of neuroendocrine and dopaminergic (DA) longitudinal axons en route to the spinal cord
	ARNT2 and SIM1 transcription factors contribute to proper positioning of Hypothalamic projections into the spinal cord (HTS)longitudinal axon tracts
	is a transcription factor involved in brain patterning and control of energy balance
	transcription factor SIM1 (single-minded 1) is important for development and function of regions of the hypothalamus that regulate energy homoeostasis and the feeding response
	is a basic helix-loop-helix Per-Arnt-Sim transcription factor that is important for neuronal development in the hypothalamus
	SIM1 is a critical yet previously unrecognized modulator of skeletal homeostasis that functions through a central relay
	has an established role in body weight homeostasis and sexual function

CELLULAR PROCESS

nucleotide, transcription

PHYSIOLOGICAL PROCESS

development

PATHWAY

metabolism

signaling

a component

heterodimerizing with ARNT2 and acting in neuroendocrine hypothalamus development

INTERACTION

DNA

RNA

small molecule

protein	cofactor of ARNT2 (are required for expression of POU3F2 during hypothalamic development)
	MAGED1 binds and positively regulates the transcriptional activity of family members SIM1, SIM2, NPAS4 and ARNT2, but does not interact with AHR, HIF1A and ARNT
	melanocortin signaling via the MC4R on SIM1 neurons implicated in the central control of male sexual behavior

cell & other

REGULATION

Other

regulated by neural protein OLIG2 (OLIG2 acts upstream of the transcriptional regulator SIM1 to specify diencephalic dopaminergic neuron)

ASSOCIATED DISORDERS

corresponding disease(s)

DEL6QP

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional       loss of function postnatal CNS deficiency of SIM1 is sufficient to cause hyperphagic obesity (Tolson 2010) constitutional       loss of function causes early-onset obesity constitutional germinal mutation     loss of function in overweight children with developmental delay

Susceptibility

to erectile dysfunction to obesity associated with lower preference for high sugar and low fat

Variant & Polymorphism SNP	rs17185536-T significantly associated with the risk of erectile dysfunction
	SIM1 variant, p.D134N, associated to obesity associated with lower preference for high sugar and low fat

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	murine S-/- die perinatally, Sim+/- development early-onset obesity, with hyperphagy but not decrease of energy expenditure
	Sim1-overexpressing transgenic mice exhibit decreased bone formation and low bone mass
	paraventricular nucleus (PVN)-Sim1 neuron ablated mice have a decreased response to fasting-induced hyperphagia