View source for Neuregulin

{{short description|Family of four EGF proteins}}
{{Infobox protein family
| Symbol = Neuregulin
| Name = Neuregulin family
| image = PDB 1hrf EBI.jpg
| width = 
| caption = Structure of the epidermal growth factor-like domain of heregulin-alpha, a ligand for p180erbB-4.<ref name="pmid8062828">{{cite journal |author=Nagata K |title=Solution structure of the epidermal growth factor-like domain of heregulin-alpha, a ligand for p180erbB-4 |journal=EMBO J. |volume=13 |issue=15 |pages=3517–23 |date=August 1994 |pmid=8062828 |pmc=395255 |doi= 10.1002/j.1460-2075.1994.tb06658.x|name-list-style=vanc|author2=Kohda D |author3=Hatanaka H |display-authors=3 |last4=Ichikawa |first4=S |last5=Matsuda |first5=S |last6=Yamamoto |first6=T |last7=Suzuki |first7=A |last8=Inagaki |first8=F}}</ref>
| Pfam = PF02158
| InterPro = IPR002154
| SMART = 
| PROSITE = 
| SCOP = 1hrf
| TCDB = 
| OPM family = 
| OPM protein = 
| PDB = {{PDB2|1hae}}, {{PDB2|1haf}}, {{PDB2|1hre}}, {{PDB2|1hrf}}
}}
'''Neuregulins''' are a family of four structurally related proteins that are part of the [[epidermal growth factor family|EGF family]] of proteins. These proteins have been shown to have diverse functions in the development of the [[nervous system]] and play multiple essential roles in vertebrate [[embryogenesis]] including: [[cardiac]] development, [[Schwann cell]] and [[oligodendrocyte]] differentiation, some aspects of neuronal development, as well as the formation of [[neuromuscular]] [[synapses]].<ref name="PUB00004928">{{cite journal |vauthors=Vartanian T, Fischbach G, Miller R |title=Failure of spinal cord oligodendrocyte development in mice lacking neuregulin |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue=2 |pages=731–5 |year=1999 |pmid=9892702 |doi=10.1073/pnas.96.2.731 |pmc=15205|doi-access=free |bibcode=1999PNAS...96..731V }}</ref><ref name="PUB00004316">{{cite journal |vauthors=Yarden Y, Burden S |title=Neuregulins and their receptors: a versatile signaling module in organogenesis and oncogenesis |journal=Neuron |volume=18 |issue=6 |pages=847–55 |year=1997 |pmid=9208852 |doi=10.1016/S0896-6273(00)80324-4|doi-access=free }}</ref>

Included in the family are [[heregulin]]; neu differentiation factor; acetylcholine receptor synthesis stimulator; glial growth factor; and sensory and motor-neuron derived factor.<ref name="PUB00003030">{{cite journal |vauthors=Schroering A, Carey DJ |title=Sensory and motor neuron-derived factor is a transmembrane heregulin that is expressed on the plasma membrane with the active domain exposed to the extracellular environment |journal=J. Biol. Chem. |volume=273 |issue=46 |pages=30643–50 |year=1998 |pmid=9804837 |doi=10.1074/jbc.273.46.30643|doi-access=free }}</ref> Multiple family members are generated by [[alternate splicing]] or by use of several cell type-specific [[transcription initiation]] sites. In general, they bind to and activate the [[Epidermal growth factor receptor|erbB family of receptor tyrosine kinases]] ([[erbB2]] (HER2), [[erbB3]] (HER3), and [[erbB4]] (HER4)), functioning both as heterodimers and homodimers.

==Neuregulin family members==
The neuregulin family includes:
* '''[[Neuregulin 1]]''' ('''NRG1'''), with numerous discovered [[isoform]]s stemming from [[alternative splicing]]:
** '''Type I NRG1'''; alternative names: Heregulin, NEU differentiation factor (NDF), or acetylcholine receptor inducing activity (ARIA)
** '''Type II NRG1'''; alternative name: Glial Growth Factor-2 (GGF2);
** '''Type III NRG1'''; alternative name: Sensory and motor neuron-derived factor (SMDF);
** '''Type IV NRG1''';
** '''Type V NRG1''';
** '''Type VI NRG1'''; Types IV-VI are proteins with 3 novel N-terminal domains identified in 2004.<!--

--><ref name="pmid15527969">{{cite journal |vauthors=Steinthorsdottir V, Stefansson H, Ghosh S, Birgisdottir B, Bjornsdottir S, Fasquel AC, Olafsson O, Stefansson K, Gulcher JR |title=Multiple novel transcription initiation sites for NRG1 |journal=Gene |volume=342 |issue=1 |pages=97–105 |year=2004 |pmid=15527969 |doi=10.1016/j.gene.2004.07.029}}</ref><!--

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* '''[[NRG2|Neuregulin 2]]''' ('''NRG2''');
* '''[[NRG3|Neuregulin 3]]''' ('''NRG3''');
* '''[[NRG4|Neuregulin 4]]''' ('''NRG4''');

In mammals, neuregulin family members are the products of 4 genes [[NRG1]], [[NRG2]], [[NRG3]] and [[NRG4]] respectively.

The transmembrane forms of neuregulin 1 (NRG1) are present within synaptic vesicles, including those containing glutamate.<ref name="PUB00009788">{{cite journal |vauthors=Lemke G, Zhou M, Ghosh S, Harvey RP, Gulcher JR, Stefansson K, Gurney ME, Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Birgisdottir B, Jonsson H, Gudnadottir VG, Gudmundsdottir E, Bjornsson A, Ingvarsson B, Ingason A, Sigfusson S, Hardardottir H, Lai D, Brunner D, Mutel V, Gonzalo A, Sainz J, Johannesson G, Andresson T, Gudbjartsson D, Manolescu A, Frigge ML, Kong A, Petursson H |title=Neuregulin 1 and susceptibility to schizophrenia |journal=Am. J. Hum. Genet. |volume=71 |issue=4 |pages=877–892 |year=2002 |pmid=12145742 |doi=10.1086/342734 |pmc=378543}}</ref> After [[exocytosis]], NRG1 is in the presynaptic membrane, where the ectodomain of NRG1 may be cleaved off. The ectodomain then migrates across the synaptic cleft and binds to and activates a member of the EGF-receptor family on the postsynaptic membrane. This has been shown to increase the expression of certain glutamate-receptor subunits. NRG1 appears to signal for glutamate-receptor subunit expression, localization, and /or phosphorylation facilitating subsequent glutamate transmission.

The NRG1 gene has been identified as a potential gene determining susceptibility to schizophrenia by a combination of genetic linkage and association approaches.<ref name="PUB00009788" />

==NRG1==
NRG1 plays a role in [[synapse]] development, influencing the [[upregulation]] of [[acetylcholine receptor]] genes beneath the endplate after mammalian [[motor neurons]] have made synaptic contact with muscle fibres, hence its alternative name ARIA = '''A'''cetylcholine '''R'''eceptor '''I'''nducing '''A'''ctivity.

== Animal models ==
A study done on mice in early 2009 has indicated that when [[neuregulin-1]]\[[ErbB]] signalling is disrupted, the [[dendrite|dendritic spines]] of neurons grow but do not fully form. This produced no immediate noticeable changes to brain development, but in adults there was a reduction of dendritic spines on neurons.<!--

--><ref name="urlHow Microscopic Changes To Brain Cause Schizophrenic Behavior In Mice">{{cite web |url=https://www.sciencedaily.com/releases/2009/02/090219121329.htm |title=How Microscopic Changes To Brain Cause Schizophrenic Behavior In Mice }}</ref><ref name="pmid19240213">{{cite journal |vauthors=Barros CS, Calabrese B, Chamero P, Roberts AJ, Korzus E, Lloyd K, Stowers L, Mayford M, Halpain S, Müller U |title=Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system |journal=[[Proc. Natl. Acad. Sci. U.S.A.]] |volume= 106|issue= 11|pages= 4507–4512|date=February 2009 |pmid=19240213 |doi=10.1073/pnas.0900355106 |pmc=2657442|doi-access=free |bibcode=2009PNAS..106.4507B }}</ref><!--

--> Glutamatergic signalling was markedly disrupted in the mice as a result of the experiment.

== In fish, birds, and earthworms ==
NRG-1,2,3 have been found in fish and birds.

mRNA similar to mammalian Pro-NRG2 precursor has been found in ''humus earthworm'' [[Lumbricidae]].

== References ==
{{reflist}}

== External links ==
* {{MeshName|Neuregulins}}

{{Neurotrophic factors}}
{{Growth factor receptor modulators}}

[[Category:Developmental neuroscience]]
[[Category:Neurotrophic factors]]