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FLASH GENE

Symbol

NRG1

contributors: mct/shn - updated : 03-08-2015

HGNC name	neuregulin 1
HGNC id	7997

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	SCZD6 schizophrenia 6
Location	8p12      Physical location : 31.497.267 - 32.622.558
Synonym name	glial growth factor
	neu differentiation factor
	heregulin, alpha (45kD, ERBB2 p185-activator)
	sensory and motor neuron derived factor
	neuregulin 1 isoform HRG-gamma
	pro-neuregulin-1, membrane-bound isoform
Synonym symbol(s)	NDF, HGL, HRGA, GGF, SMDF, ARIA, GGF2, HRG, HRG1, Pro-NRG1, MST131

DNA

TYPE	functioning gene
STRUCTURE	1125.74 kb     13 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

Y

status

provisional

Map	pter - D8S1810 - D8S2319 - NRG1 - D8S1758 - D8S259 - cen

RNA

TRANSCRIPTS	type	messenger

text	other alternative forms

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004495 6 splicing 1694 NP_004486 22.6 211 - 1992 1350381 also called HRG-gamma NM_013962 5 splicing 1987 NP_039256 45 422 nervous system, skeletal muscle 1993 8096067 soluble form also called GGFHBS5 or GGF2 NM_013959 3 splicing 2374 NP_039253 31 296 in the nervous system spinal cord, motoneuron, fetal lung, liver, kidney 2004 15044753 also called SMDF a C-terminal EGF-like domain and a unique N-terminal sequence which lacks an Ig-like domain, cysteine-rich domain (CRD) NM_013964 12 splicing 3078 NP_039258 70.2 640 breast, ovary, testis, prostate, heart, muscle 2004 15044753 also called erbB2 or HRG-alpha NM_001160008 11 splicing 2377 NP_001153480 - 420 - 1992 1350381 also called HRG-beta2b NM_013957 12 splicing 3069 NP_039251 70 637 - 1992 1350381 also called HRG-beta 2 NM_013958 7 splicing 1740 NP_039252 26 241 brain spinal cord 1993 8096067 may be a nuclear isoform also called HRG-beta 3, GGF or GGFHFB1 NM_013960 13 splicing 3220 NP_039254 51 462 - 1994 7509448 also called ndf43 or HRG-beta 1 NM_013956 13 - 3093 NP_039250 - 645 - 1992 1350381 also called HRG-beta1 NM_001160007 4 splicing 1592 NP_001153479 - 177 - 1992 1350381 also called HRG-gamma3 NM_001160005 5 splicing 1638 NP_001153477 - 207 - 1992 1350381 also called HRG-beta3b NM_001160004 13 splicing 3211 NP_001153476 - 459 - 1992 1350381 also called ndf43b NM_001160002 5 splicing 1643 NP_001153474 - 194 - 1992 1350381 also called HRG-gamma2 NM_001160001 11 splicing 2502 NP_001153473 - 590 - 1992 1350381 also called HRG-beta1d NM_001159999 13 splicing 2604 NP_001153471 - 624 - 1998 9491987 also called HRG-beta1b promotes breast cancer cell proliferation through RAC1/ERK-dependent induction of CCND1 and CDKN1A NM_001159995 12 splicing 2553 NP_001153467 - 607 - 1992 1350381 also called HRG-beta1c NM_001159996 9 splicing 2411 NP_001153468 - 308 - 1992 1350381 also called ndf43c

EXPRESSION

Type

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine large intestine colon     Homo sapiens Reproductive female system breast

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Membrane mucous membrane       Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron Reproductive epithelial cell

cell lineage
cell lines
fluid/secretion	cerebral spinal fluid

at STAGE

physiological period

embryo

Text	embryonic tissues

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	NRG1 type 1, immunoglobulin-like and EGF-like domain
	a kringle-like sequence

conjugated

GlycoP

isoforms

Precursor

precursors are expressed predominately within cortical neurons, soluble neuregulin accumulates preferentially on the surface of white matter astrocytes (PMID: 19150438)

HOMOLOGY

interspecies	ortholog to Nrg1, Mus musculus
	ortholog to Nrg1, Rattus norvegicus
	ortholog to nrg1, Danio rerio

Homologene

FAMILY

neuregulin family

CATEGORY

regulatory , signaling growth factor

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm
	intracellular,nucleus
text	type I membrane protein or soluble form

basic FUNCTION	required for generation of neural crest-derived neurons in cranial ganglia and for trabeculation of the heart ventricle (
	essential role of CRD-NRG-1-mediated signaling for coordinating nerve, target, and Schwann cell interactions in the normal maintenance of peripheral synapses (
	role in muscle spindle differentiation (
	indirect NEU/ERBB2 p185 activator (see ERBB2)
	regulator of expression of ligand and voltage gated channels in neurons and skeletal muscle, stimulating glucose transport translocation and transporter expression in muscle cells, essential for trabeculation of cardiac ventricle
	involved in the myelination and regulating axonal myelin sheath thickness
	promoting cell death of prostate cancer cells
	may regulate skeletal myogenesis and this regulation is dependent on the state of differentiation of the myocytes
	required for spermatogonial amplification and differentiation
	plays an important role in oncogenesis
	induces glial cell line-derived neurotrophic growth factor-independent, non-branching growth and differentiation of ureteric bud epithelia
	may also play a key role in the proliferation of neuronal progenitors in CNS development (regulate proliferation but not apoptosis)
	plays critical roles in the development of the embryonic cerebral cortex via regulation of cortical cell migration and patterning
	development of oligodendrocytes and neurones from olig2-expressing precursor cells (
	role in the signaling network implicated in enteric nervous system development and maintenance which is also in line with its role as a modifier of the RET gene
	NRG1 signaling is functional and cytoprotective in brain microvascular endothelial cells
	playing a plays a critical role in myelination that is regulatrd by ERBB2 and ERBB2IP
	is a novel mediator of MUC5AC and MUC5B expression in bronchial epithelial cells
	may be the principal tumour suppressor gene that leads to the loss of 8p in many breast and other epithelial cancers
	like NRG3, plays critical roles in the development of the embryonic cerebral cortex via regulation of cortical cell migration and patterning
	stimulates the formation of new synapses and strengthens existing synapses and may be critical for basal synapse formation
	exerts its signaling activity by binding to its cognate receptors, ERBB2/ERBB3 heterodimers or ERBB4 homodimers
	zebrafish Neuregulin 1 controls Schwann cell migration and is required in neurons for migration
	new role for NRG1/ERBB4 signaling in regulating oligodendrocyte precursors migration selectively during early stages of CNS development
	is an axon-derived factor that is critical for Schwann cell (SC) development and myelinogenesis in a manner dependent on transmembrane tyrosine kinases ERBB2 and ERBB3
	mediates the glucose repression of multiple genes through its direct binding to the specific promoter regions
	potential role for NRG3 in brain development and function, which appears to be distinct from its paralog NRG1
	NRG1 selectively increases GRM1-activated currents by inducing synthesis and trafficking to membrane of functional receptors

CELLULAR PROCESS	cell life, differentiation
	cell life, proliferation/growth

PHYSIOLOGICAL PROCESS

synaptogenesis

PATHWAY

metabolism

signaling

autocrine signaling loop between NOTCH1 and NRG1 that controls melanoma growth

a component

INTERACTION

DNA

RNA

small molecule

protein	Her2 and Her3 (
	epidermal growth factor, EGF (
	LIM kinase 1, LIMK1 (
	activating their tyrosine kinase receptor (ERBB2-4), enhancer of CHRND, CHRNE in muscle enhancer of GRIN2C, CHRNA7 in neurons
	ERBB4
	GDNF (required for effective formation of long spermatogonial chain)
	link between GJB1 expression and NRG1 regulation of Schwann cells proliferation that does not involve GJB1-mediated intercellular communication
	interacting with BACE1 (processing of NRG1 by BACE1 rather than ADAM10 is more critical for the regulation of myelination)
	PARD3 regulates RAC1 activation by BDNF but not by NRG1-Type III in Schwann cells, although both ligands activate RAC1
	NRG/ERBB signaling maintains high efficacy of synaptic transmission by stabilizing the postsynaptic apparatus via phosphorylation of DTNA
	NOTCH1 directly regulates the transcription of NRG1 by binding to its promoter region
	NRG1 is the ligand for ERBB3 and 4, members of the epidermal growth factor family of receptors that are involved in the genesis and progression of a number of cancers
	ERBIN is required for remyelination of regenerated axons after injury, probably by regulating ERBB2 and NRG1 levels
	induces expression of the muscle spindle-specific gene EGR3 by stimulating the transcriptional activity of CREB1 and SRF
	NRG1 inhibited the GDNF-induced neuronal differentiation and GDNF negatively regulated NRG1-signaling by down-regulating the expression of its receptor, ERBB2
	NRG1 signaling promotes dendritic spine growth through kalirin
	imbalanced NRG1 isoforms and downregulated ERBIN may contribute to the dysregulation of ERBB2 signaling in the development of diabetic peripheral neuropathy (DPN)

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

SCZD6

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional fusion       chimeric protein gamma heregulin (ERBG) by fusion with STIP1 (5'-STIP1-NRG1-3') in translocation t(8;11) (p12;q13 constitutional     --low   in amyotrophic lateral sclerosis and Parkinson's disease, in cerebral fluid constitutional     --over   in Alzheimer's disease tumoral         silenced by methylation in breast cancers

Susceptibility

to schizophrenia ( to late onset Alzheimer's disease with psychoses to Hirschsprung's disease

Variant & Polymorphism SNP	increasing the risk of late onset Alzheimer's disease families with psychoses
	SNP increasing the risk of schizophrenia
	interaction between variants in NRG1 and ERBB4 might contribute to susceptibility for schizophrenia
	SNP increasing the risk of Hirschsprung's disease

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cardiovascular aquired heart failure potential use of NRG1s as novel therapy for heart failure respiratory lung   may represent a novel therapeutic target for mucus hypersecretion in respiratory diseases

ANIMAL & CELL MODELS

	in cysteine-rich domain-NRG-1-/-mice, peripheral projections defasciculated and displayed aberrant branching patterns within their targets (
	knock-down of nrg1 caused near total loss of olig2-positive cerebellar neurones, but caused no apparent loss of spinal motor neurones (
	misexpression of human NRG1 type III in zebrafish transgenic embryos results in ectopic Schwann cell migration, allowing them to aberrantly enter the central nervous system
	in murine juvenile testes Ra and Fsh induced meiosis indirectly through Sertoli cells when Nrg1 and Nrg3 were upregulated, as Nrg1 amplified itself and Nrg3