Neuregulin
Encyclopedia
The Neuregulins are a family of four structurally-related proteins that are part of the 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.
Included in the family are heregulin; neu differentiation factor; acetylcholine receptor synthesis stimulator; glial growth factor; and sensory and motor-neuron derived factor. 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 erbB family of receptor tyrosine kinases
(erbB2 (HER2), erbB3
(HER3), and erbB4
(HER4)), functioning both as heterodimers and homodimers.
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. 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.
development, influencing the upregulation of acetylcholine receptor
genes beneath the endplate after mammalian motor neurons have made synaptic contact with muscle fibres, hence its name ARIA = Acetylcholine Receptor Inducing Activity.
signalling is disrupted, the dendritic spines
of neurons grow but do not fully form. This produced no immediate noticeable changes to brain development, but it was found eventually that abnormalities were observed that mirrored those of the schizophrenic brain and were accompanied by similar symptoms to the disease when these manifested. This parallels the time delay for symptoms setting in with schizophrenic humans who usually appear to show normal development until early adulthood. Glutamatergic signalling was markedly disrupted in the mice as a result of the experiment, possibly lending support to the glutamate hypothesis of schizophrenia
.
mRNA similar to mammalian Pro-NRG2 precursor has been found in humus earthworm Lumbricidae
.
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
and play multiple essential roles in vertebrate embryogenesis
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
including: cardiac development, Schwann cell
Schwann cell
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system . Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle...
and oligodendrocyte
Oligodendrocyte
Oligodendrocytes , or oligodendroglia , are a type of brain cell. They are a variety of neuroglia. Their main function is the insulation of axons in the central nervous system of some vertebrates...
differentiation, some aspects of neuronal development, as well as the formation of neuromuscular synapses.
Included in the family are heregulin; neu differentiation factor; acetylcholine receptor synthesis stimulator; glial growth factor; and sensory and motor-neuron derived factor. 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 erbB family of receptor tyrosine kinases
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(erbB2 (HER2), erbB3
ERBB3
Receptor tyrosine-protein kinase erbB-3 is an enzyme that in humans is encoded by the ERBB3 gene.It is thought that ERBB3, when activated, becomes a substrate for dimerization and subsequent phosphorylation by ERBB1, ERBB2 and ERBB4....
(HER3), and erbB4
ERBB4
Receptor tyrosine-protein kinase erbB-4 is an enzyme that in humans is encoded by the ERBB4 gene. Alternatively spliced variants that encode different protein isoforms have been described; however, not all variants have been fully characterized....
(HER4)), functioning both as heterodimers and homodimers.
Neuregulin family members
The neuregulin family includes:- Neuregulin-1Neuregulin 1Neuregulin 1 or NRG1 is a protein which in humans is encoded by the NRG1 gene. NRG1 is one of four proteins in the neuregulin family that act on the EGFR family of receptors. Neuregulin 1 is produced in numerous isoforms by alternative splicing, which allows it to perform a wide variety of functions...
(NRG1), with numerous discovered isoforms stemming from alternative splicingAlternative splicingAlternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA 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.
- Neuregulin-2NRG2Neuregulin 2, also known as NRG2, is a protein which in humans is encoded by the NRG2 gene.- Function :Neuregulin 2 is a novel member of the neuregulin family of growth and differentiation factors. Through interaction with the ErbB family of receptors, NRG2 induces the growth and differentiation...
(NRG2); - Neuregulin-3NRG3Neuregulin 3 also known as NRG3 is a member of the neuregulin protein family which in humans is encoded by the NRG3 gene.- Function :...
(NRG3); - Neuregulin-4NRG4Neuregulin 4 also known as NRG4 is a member of the neuregulin protein family which in humans is encoded by the NRG4 gene.-Function:...
(NRG4);
In mammals, neuregulin family members are the products of 4 genes NRG1, NRG2
NRG2
Neuregulin 2, also known as NRG2, is a protein which in humans is encoded by the NRG2 gene.- Function :Neuregulin 2 is a novel member of the neuregulin family of growth and differentiation factors. Through interaction with the ErbB family of receptors, NRG2 induces the growth and differentiation...
, NRG3
NRG3
Neuregulin 3 also known as NRG3 is a member of the neuregulin protein family which in humans is encoded by the NRG3 gene.- Function :...
and NRG4
NRG4
Neuregulin 4 also known as NRG4 is a member of the neuregulin protein family which in humans is encoded by the NRG4 gene.-Function:...
respectively.
The transmembrane forms of neuregulin 1 (NRG1) are present within synaptic vesicles, including those containing glutamate. After exocytosis
Exocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...
, 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.
ARIA
ARIA plays a role in synapseSynapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
development, influencing the upregulation of acetylcholine receptor
Acetylcholine receptor
An acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.-Classification:...
genes beneath the endplate after mammalian motor neurons have made synaptic contact with muscle fibres, hence its name ARIA = Acetylcholine Receptor Inducing Activity.
Animal models of schizophrenia
A study done on mice in early 2009 has indicated that when neuregulin-1\ErbBErbB
The ErbB protein family or epidermal growth factor receptor family is a family of four structurally related receptor tyrosine kinases. The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: Erythroblastic Leukemia Viral Oncogene...
signalling is disrupted, the dendritic spines
Dendrite
Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project...
of neurons grow but do not fully form. This produced no immediate noticeable changes to brain development, but it was found eventually that abnormalities were observed that mirrored those of the schizophrenic brain and were accompanied by similar symptoms to the disease when these manifested. This parallels the time delay for symptoms setting in with schizophrenic humans who usually appear to show normal development until early adulthood. Glutamatergic signalling was markedly disrupted in the mice as a result of the experiment, possibly lending support to the glutamate hypothesis of schizophrenia
Glutamate hypothesis of schizophrenia
The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors...
.
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
Lumbricidae
The Lumbricidae is a family of earthworms which includes most of the earthworm species well known to Europeans. About 33 lumbricid species have become naturalized around the world, but the bulk of the species are in Holarctic: from Canada and the United States The Lumbricidae is a family of...
.