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Neuregulins or neuroregulins 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 In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...
and play multiple essential roles in vertebrate
embryogenesis An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
including:
cardiac The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...
development,
Schwann cell Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ens ...
and
oligodendrocyte Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...
differentiation, some aspects of neuronal development, as well as the formation of
neuromuscular A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation ...
synapses. Included in the family are
heregulin Neuregulin 1, or NRG1, is a gene of the epidermal growth factor family that 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 num ...
; 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 Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...
or by use of several cell type-specific
transcription initiation Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules called ...
sites. In general, they bind to and activate the erbB family of receptor tyrosine kinases (
erbB2 Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...
(HER2),
erbB3 Receptor tyrosine-protein kinase erbB-3, also known as HER3 (human epidermal growth factor receptor 3), is a membrane bound protein that in humans is encoded by the ''ERBB3'' gene. ErbB3 is a member of the epidermal growth factor receptor (EGFR/ ...
(HER3), and
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 characteriz ...
(HER4)), functioning both as heterodimers and homodimers.


Neuregulin family members

The neuregulin family includes: *
Neuregulin-1 Neuregulin 1, or NRG1, is a gene of the epidermal growth factor family that 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 num ...
(NRG1), with numerous discovered
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...
s stemming from
alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...
: ** 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-2 (NRG2); * Neuregulin-3 (NRG3); * Neuregulin-4 (NRG4); In mammals, neuregulin family members are the products of 4 genes
NRG1 Neuregulin 1, or NRG1, is a gene of the epidermal growth factor family that 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 num ...
,
NRG2 Neuregulin 2, also known as NRG2, is a protein which in humans is encoded by the ''NRG2'' gene. Function Neuregulin 2 (NRG2) is a novel member of the neuregulin family of growth and differentiation factors. Through interaction with the ErbB f ...
,
NRG3 Neuregulin 3, also known as NRG3, is a neural-enriched member of the neuregulin protein family which in humans is encoded by the ''NRG3'' gene. The NRGs are a group of signaling proteins part of the superfamily of epidermal growth factor, EGF ...
and
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 The neuregulins, including NRG4, activate erb-b2 receptor tyrosine kinase 4 (ERBB4) to initiating cell signal ...
respectively. The transmembrane forms of neuregulin 1 (NRG1) are present within synaptic vesicles, including those containing glutamate. After
exocytosis Exocytosis () is a form of active transport and bulk transport in which a cell transports molecules (e.g., neurotransmitters and proteins) out of the cell ('' exo-'' + ''cytosis''). As an active transport mechanism, exocytosis requires the use o ...
, 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.


NRG1

NRG1 plays a role in
synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...
development, influencing the
upregulation In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proc ...
of
acetylcholine receptor An acetylcholine receptor (abbreviated AChR) is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter. Classification Like other transmembrane receptors, acetylcholine receptors are classified according ...
genes beneath the endplate after mammalian
motor neurons A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectly ...
have made synaptic contact with muscle fibres, hence its alternative name ARIA = Acetylcholine Receptor Inducing Activity.


Animal models

A study done on mice in early 2009 has indicated that when
neuregulin-1 Neuregulin 1, or NRG1, is a gene of the epidermal growth factor family that 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 num ...
\
ErbB The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1 (EGFR, ErbB1), Her2 (Neu, ErbB2), Her3 ( ...
signalling is disrupted, the
dendritic spines A dendritic spine (or spine) is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical si ...
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. 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 The Lumbricidae are a family of earthworms. About 33 lumbricid species have become naturalized around the world, but the bulk of the species are in the Holarctic region: from Canada (e.g. ''Bimastos lawrenceae'' on Vancouver Island) and the Uni ...
.


References


External links

* {{Growth factor receptor modulators Developmental neuroscience Neurotrophic factors