Table of contents

Neuregulin and development

The migration of neuronal precursors along radial glial fibers is a critical step in the formation of the nervous system. Neuregulin-erbB receptor signaling plays a crucial role in the migration of cerebellar granule cells along radial glial fibers. Granule cells express neuregulin (NRG), and radial glia cells express erbB4 in the developing cerebellum and in vitro. When the glial erbB receptors are blocked, neurons fail to induce radial glia formation, and their migration along radial glial fibers is impaired. Moreover, soluble NRG is as effective as neuron-glia contact in the induction of radial glia formation. These results suggest that the activation of glial erbB4 by NRG is an early critical step in the neuronal migration program (Rio, 1997).

During neuronal migration to the developing cerebral cortex, neurons regulate radial glial cell function; in turn, radial glial cells support neuronal cell migration and differentiation. To study how migrating neurons and radial glial cells influence each others' function in the developing cerebral cortex, the role of glial growth factor (a soluble form of neuregulin) was studied, in neuron-radial glial interactions. GGF is expressed by migrating cortical neurons and promotes their migration along radial glial fibers. Concurrently, GGF also promotes the maintenance and elongation of radial glial cells, which are essential for guiding neuronal migration to the cortex. In the absence of GGF signaling via erbB2 receptors, radial glial development is abnormal. GGF's regulation of radial glial development is mediated in part by brain lipid-binding protein (BLBP), a neuronally induced, radial glial molecule, previously shown to be essential for the establishment and maintenance of the radial glial fiber system. The ability of GGF to influence both neuronal migration and radial glial development in a mutually dependent manner suggests that it functions as a mediator of interactions between migrating neurons and radial glial cells in the developing cerebral cortex (Anton, 1997).

Neurotrophin 3 (NT-3) can support the survival of some embryonic sympathetic neuroblasts before they become nerve growth factor dependent. NT-3 is produced in vivo by nonneuronal cells neighboring embryonic sympathetic ganglia. NT-3 mRNA is produced by these nonneuronal cells in vitro and is up-regulated by platelet-derived growth factor, ciliary neurotrophic factor, and glial growth factor 2 (a neuregulin). Nonneuronal cell-conditioned medium promotes survival and induces TrkA expression in isolated sympathetic neuroblasts; this activity is blocked by anti-NT-3 antibody. Neuroblasts also enhance NT-3 production by nonneural cells. Neuroblasts synthesize several forms of neuregulin, and antibodies to neuregulin attenuate the effect of the neuroblasts on the nonneuronal cells. These data suggest a reciprocal cell-cell interaction, in which neuroblast-derived neuregulins promote NT-3 production by neighboring nonneuronal cells, which in turn promotes neuroblast survival and further differentiation (Verdi, 1996).

Denervated adult mammalian muscle fibers are reinnervated by regenerating axons and, in the case of partially denervated muscles, by sprouts extended from remaining, intact axons. Recent experiments suggest that Schwann cells (SCs) regulate these events, inducing and guiding axonal outgrowth through the processes they extend. Reinnervation of denervated neonatal muscles, in contrast to adult reinnervation, is deficient and axonal sprouting is absent. Neonatal denervation leads to the rapid, apoptotic death of SCs at rat neuro-muscular junctions. Injection of glial growth factor, a member of the neuregulin family of trophic factors present in developing sensory and motor neurons, prevents this apoptosis in vivo. These results provide further evidence for the importance of SCs in regulating nerve growth and suggest that axon-Schwann cell trophic interactions play a role in the normal development of the neuromuscular system (Trachtenberg, 1996).

Neuregulins (known as NDF, heregulin, GGF ARIA, or SMDF) are EGF-like growth and differentiation factors that signal through tyrosine kinase receptors of the ErbB family. A novel phenotype is described in mice with targeted mutations in either the erbB2, erbB3, or neuregulin-1 genes. These three mutations cause a severe hypoplasia of the primary sympathetic ganglion chain. Migration of neural crest cells to the mesenchyme lateral of the dorsal aorta (where they differentiate into sympathetic neurons) depends on neuregulin-1 and its receptors. Neuregulin-1 is expressed at the origin of neural crest cells. Moreover, a tight link between neuregulin-1 expression, the migratory path, and the target site of sympathogenic neural crest cells is observed. Sympathetic ganglia synthesize catecholamines in the embryo and the adult. Accordingly, catecholamine levels in mutant embryos are severely decreased; it is suggested that the lack of catecholamines contributes to the embryonal lethality of the erbB3 mutant mice. Thus, neuregulin-1, erbB2, and erbB3 are required for the formation of the sympathetic nervous system; the block in development observed in mutant mice is caused by a lack of neural crest precursor cells in the anlage of the primary sympathetic ganglion chain. Together with previous observations, these findings establish the neuregulin signaling system as a key regulator in the development of neural crest cells (Britsch, 1998).

The distribution of neuregulin and its transmembrane precursor was mapped in developing, embryonic chick and mouse spinal cord. Neuregulin mRNA and protein are expressed in motor and sensory neurons shortly after their birth and levels steadily increase during development. Expression of the neuregulin precursor is highest in motor and sensory neuron cell bodies and axons; soluble, released neuregulin accumulates along early motor and sensory axons, radial glia, spinal axonal tracts and neuroepithelial cells through associations with heparan sulfate proteoglycans. Neuregulin accumulation in the synaptic basal lamina of neuromuscular junctions occurs significantly later, coincident with a reorganization of muscle extracellular matrix resulting in a relative concentration of heparan sulfate proteoglycans at endplates. These results demonstrate an early axonal presence of neuregulin and its transmembrane precursor at developing synapses and a role for heparan sulfate proteoglycans in regulating the temporal and spatial sites of soluble neuregulin accumulation during development (Loeb, 1999).

While a majority of proNRG message and protein is localized to motor and sensory neuron cell bodies and axons, antisera against the NH2-terminal extracellular domain stains additional structures, including axonal tracts, radial glia and neuroepithelia. Most of this immunoreactivity is released by high salt or an enzyme that specifically degrades heparan sulfate, suggesting that a majority of this immunoreactivity reflects NRG associated with HSPGs. This finding is consistent with observations that NRG protein and tyrosine phosphorylation activity are released from the surface of freshly dissociated chick spinal cord by high salt, heparin or selective proteolytic cleavage of the Ig-like domain. While NRG immunoreactivity associated with the extracellular matrix is very strong, little staining of motor and sensory neuron cell bodies is seen with antiserum. This may be due to the release of soluble NRGs into the extracellular media resulting in a depletion of the extracellular domain within cell bodies. Once expressed on the cell surface, proNRG is rapidly cleaved to release the soluble ectodomain in transfected fibroblasts. Therefore, much of the immunoreactivity seen in cell bodies may reflect the ‘stump’ or remaining cytoplasmic domain associated with the cell after proteolytic cleavage. An alternative explanation is that the antisera are recognizing NRG forms that are synthesized without the cytoplasmic and membrane-spanning sequences (Loeb, 1999 and references).

The exact role of matrix-bound NRG in the developing spinal cord is not yet clear. HSPGs have a unique role of acting as reservoirs for many other soluble growth and differentiation factors. In fact, the distribution of the heparin-binding guidance factor netrin-1 shows similarities to that of NRG in the embryonic spinal cord. NRG is thus positioned to participate in the development of early ascending, descending and commissural axons. NRGs may also interact with central and peripheral glia, known to respond to NRG for their propagation, differentiation and survival. Staining along radial glia supports recent findings documenting an important new role for the NRGs in cell migration along radial glia. Additional roles have been proposed for NRGs in cell fate determination of neural crest cells, suggesting possible effects of NRGs in the developing neuroepithelia. Later in development, as the peripheral nerves and axonal tracts within the spinal cord mature, the staining intensity decreases dramatically suggesting that many of the roles that NRG plays here may be transient (Loeb, 1999 and references).

HSPGs have been identified and localized within the developing central and peripheral nervous systems. For some, the expression patterns clearly parallel that seen here for NRG, making them good candidates for NRG-binding proteoglycans. One of these is cerebroglycan, localized in the developing embryo along motor and sensory axons, spinal axonal tracts and commissural axons. Similar to what is observed for NRG, little cerebroglycan immunoreactivity is present in motor neuron cell bodies and cerebroglycan immunoreactivity along axonal tracts becomes significantly reduced as these tracts mature. Agrin is another HSPG recently shown to be present in central and peripheral axonal tracts of the developing nervous system and may also participate in localizing soluble NRG. It seems likely HSPGs expressed at specific times during nervous system development may direct the localization of Ig-containing NRG forms to specific regions. NRG accumulation at maturing synapses may be driven by a change in the distribution of HSPGs. NRG immunoreactivity at NMJs becomes obvious relatively late in development: on E16 in the chick and around birth in mammals. This is puzzling given that NRG is expressed soon after motor neurons are born and carried to the distal ends of growing motor axons at the time of initial nerve-muscle (and nerve-glia) contact. It is suggested that soluble NRG is released from nerve endings from E2 onward; however, the dramatic rise in NRG immunoreactivity at NMJs between E16 and E18 results from a relative concentration of HSPGs in the synaptic basal lamina. Consistently, a dramatic change is observed in the distribution of a muscle- derived HSPG and agrin in chick ALD muscle from E14-E18. The pattern of these proteoglycans changes from a diffuse distribution along the entire muscle length to a highly restricted pattern of expression at endplates. A different anti-agrin antibody reveals a similar reduction in extrasynaptic agrin immunoreactivity with a corresponding increase at junctional sites over this same period. NRG immunoreactivity becomes progressively concentrated to synapses with a marked reduction at extrasynaptic sites over the exact same developmental time frame. This NRG immunoreactivity is pinpointed to the border zone between the lamina densa and lamina lucida, close to the nerve terminal from where it is likely released. This region of the basal lamina has been shown to contain the negatively charged glycosaminoglycan side chains of HSPGs which may serve to concentrate NRGs. HSPG that becomes highly concentrated at synapses is almost exclusively derived from muscle. This suggests that the deposition of HSPGs at NMJs may be a selective way by which a given muscle can regulate NRG accumulation at its own synapses (Loeb, 1999 and references).

The exact functional role of this relatively late concentration of NRG at NMJs remains to be determined. Ig-like domain-containing isoforms are clearly important functionally in synapse development and maturation, because mice with specific disruptions of this domain fail to function properly. One possible role of this late appearance comes from an analysis of AChR distribution in embryonic chick posterior latissimus dorsi muscle revealing that a rapid loss of extrajunctional receptors occurs by an activity-dependent process between E17 and E19. This correlates precisely to when both NRG and HSPGs accumulate at endplates with a corresponding reduction in these proteins at extrajunctional sites. The restriction of HSPGs and NRG to synaptic sites, therefore, may restrict AChR synthesis to muscle subsynaptic nuclei and result in less NRG activity and AChR synthesis at extrajunctional sites. HSPG deposition in the synaptic basal lamina may influence synapse maturation by providing a stable, concentrated source of NRG (Loeb, 1999 and references).

Neu differentiation factor (NDF), a member of the neuregulin ligand family of erbB receptors, induces both differentiative and mitogenic effects on cultured human mammary epithelial cells. Expression of NDF was targeted to the mammary gland of transgenic mice using the mouse mammary tumor virus (MMTV) promoter in a fusion construct. There was a clear, but subtle effect on development of the adult virgin gland in female transgenic animals. Terminal end bud structures (TEBs), which normally disappear from the mammary gland at the age of approximately 8 weeks in wild type mice, persist in glands of virgin MMTV-NDF transgenic females, suggesting that NDF inhibits signals that normally lead to the terminal differentiation of these structures. Further, female mice, bred continuously to maximize expression of the transgene in the mammary gland, develop mammary adenocarcinomas at a median age of 12 months. Since these tumors arise in a solitary fashion, it is inferred that NDF is necessary, but not sufficient for their formation. In order to explore the signal transduction pathways potentially activated by NDF, expression of the receptors erbB2, erbB3 and erbB4 was examined in mammary epithelial cells established from an NDF-induced tumor. All three receptors were expressed, though only the erbB3 receptor was phosphorylated, suggesting that overexpression of NDF might operate through this receptor. Additionally, about 50% of MMTV-NDF transgenic mice developed Harderian (lachrymal) gland hyperplasia, a benign tumor that does not progress to frank malignancy (Krane, 1996).

In organ cultures of mammary glands, hepatocyte growth factor (HGF, scatter factor) promotes branching of the ductal trees but inhibits the production of secretory proteins. Neuregulin (NRG, neu differentiation factor) stimulates lobulo-alveolar budding and the production of milk proteins. These functional effects are paralleled by the expression of the two factors in vivo: HGF is produced in mesenchymal cells during ductal branching in the virgin animal; NRG is expressed in the mesenchyme during lobulo-alveolar development at pregnancy. The receptors of HGF and NRG (c-met, c-erbB3, and c-erbB4), which are expressed in the epithelial cells, are not regulated. In organ culture, branching morphogenesis and lobulo-alveolar differentiation of the mammary gland can be abolished by blocking expression of endogenous HGF and NRG by the respective antisense oligonucleotides; in antisense oligonucleotide-treated glands, morphogenesis can again be induced by the addition of recombinant HGF and NRG. Thus two major postnatal morphogenic periods of mammary gland development are dependent on sequential mesenchymal-epithelial interactions mediated by HGF and NRG (Yang, 1995).

Neuregulins are a family of growth factors that has been shown to promote the growth or differentiation of various cell types. Targeted mutations of the genes for neuregulins or their putative receptors by homologous recombination result in embryonic lethality characterized by cardiac malformation. A role for neuregulin in the growth of cultured chick heart cells has been investigated. Neuregulin induces the tyrosine phosphorylation of a 185-kDa protein in cultured heart cells; it also stimulates an increase in [(3)H]thymidine incorporation and BrDU labeling in the cell cultures. Immunocytochemistry reveals that the increased DNA synthesis is primarily in mesenchymal cells and not detected in myocytes or endocardial cells. These data suggest that neuregulin may function as a paracrine signal in mesenchymal-endothelial interactions during cardiac development (Ford, 1999).

Neuregulin, or neu differentiation factor, induces cell proliferation or differentiation through interaction with members of the ErbB family of receptor tyrosine kinases. Neuregulin can also induce profound morphogenic responses in cultured epithelial cells of different origins. These effects include scattering of small epithelial islands and rearrangement of larger cell islands into ordered ring-shaped arrays with internal lumens. The ring-forming cells are interconnected by cadherin- and beta-catenin-containing adherens junctions. In confluent cultures, neuregulin treatment induces formation of circular lumenlike gaps in the monolayer. Both cell scattering and ring formation are accompanied by a marked increase in cell motility that is independent of hepatocyte growth factor/scatter factor and its receptor (c-Met). Affinity-labeling experiments imply that a combination of ErbB-2 with ErbB-3 mediates the morphogenic signal of neuregulin in gastric cells. Indeed, a similar morphogenic effect can be reconstituted in nonresponsive cells by coexpression of ErbB-2 and -3. It is concluded that a heterodimer between the kinase-defective neuregulin receptor, ErbB-3, and the coreceptor, ErbB-2, mediates the morphogenetic action of neuregulin (Chausovsky, 1998).

Newly formed oligodendrocytes depend on axons for their survival, but the nature of the axon-derived survival signal(s) remains unknown. Neuregulin (NRG) supports the survival of purified oligodendrocytes and aged oligodendrocyte precursor cells (OPCs) but not of young OPCs. Axons promote the survival of purified oligodendrocytes and this effect is inhibited if NRG is neutralized. In the developing rat optic nerve, evidence is provided that delivery of NRG decreases both normal oligodendrocyte death and the extra oligodendrocyte death induced by nerve transection, whereas neutralization of endogenous NRG increases the normal death. These results suggest that NRG is an axon-associated survival signal for developing oligodendrocytes (Fernandez, 2000).

NRG is unlikely to be the only neuron-derived signal that promotes oligodendrocyte survival in the developing CNS, because antibodies directed against alpha6 beta1 integrin on the surface of oligodendrocytes inhibit the survival-promoting effects of DRG neurons in DRG oligodendrocyte cocultures. The nature of the putative neuron-derived ligand recognized by the integrin is unknown, but laminin-2 is a strong candidate. Moreover, in addition to neurons, astrocytes also make cytokines and growth factors that can promote the survival of oligodendrocyte lineage cells both in vitro and in vivo. The relative importance of these factors in promoting the survival of oligodendrocytes in the developing optic nerve is uncertain. One possibility is that newly formed oligodendrocytes depend for their survival mainly on astrocyte-derived factors such as PDGF, whereas more mature oligodendrocytes depend mainly on axon-derived factors such as NRG. PDGF, for example, promotes the survival of newly formed oligodendrocytes, but the cells quickly lose their PDGF receptors and so can no longer respond. Future studies that inactivate the factors individually and in various combinations will ultimately be required to sort out their relative contributions to oligodendrocyte survival in vivo (Fernandez, 2000).

Many steps of peripheral glia development appear to be regulated by neuregulin1 (NRG1) signaling but the exact roles of the different NRG1 isoforms in these processes remain to be determined. While glial growth factor 2 (GGF2), a NRG1 type II isoform, is able to induce a satellite glial fate in neural crest stem cells, targeted mutations in mice have revealed a prominent role of NRG1 type III isoforms in supporting survival of Schwann cells at early developmental stages. The role of NRG1 isoforms in the differentiation of Schwann cells from neural crest-derived progenitor cells was investigated. In multipotent cells isolated from dorsal root ganglia, soluble NRG1 isoforms do not promote Schwann cell features, whereas signaling by membrane-associated NRG1 type III induces the expression of the Schwann cell markers Oct-6/SCIP and S100 in neighboring cells, independent of survival. Thus, axon-bound NRG1 might actively promote both Schwann cell survival and differentiation (Leimeroth, 2002).

The Cre-LoxP system was used to establish erbB2 conditional mutant mice in order to investigate the role of erbB2 in postnatal development of the enteric nervous system. The erbB2/nestin-Cre conditional mutants exhibit retarded growth, distended colons, and premature death, resembling human Hirschsprung's disease. Enteric neurons and glia are present at birth in the colon of erbB2/nestin-Cre mutants; however, a marked loss of multiple classes of enteric neurons and glia occurs by 3 weeks of age. Furthermore, the requirement for erbB2 in maintaining the enteric nervous system is not cell autonomous, but rather erbB2 signaling in the colonic epithelia is required for the postnatal survival of enteric neurons and glia (Crone, 2003).

The enteric nervous system (ENS) is a complex network of interconnected neurons that control intestinal motility, exocrine and endocrine secretion, blood flow, immune responses, and uptake of nutrients in the gastrointestinal tract. The ENS has been likened to a second 'brain' in that it is the only part of the peripheral nervous system that can function in the absence of innervation by the central nervous system. The formation of the ENS occurs through migration and differentiation of neural crest-derived progenitor cells, which are influenced by their interaction with microenvironmental factors to differentiate into sensory neurons, motor neurons, interneurons, or enteric glia. The neurons of the ENS are grouped into interconnected ganglia which form the myenteric (Auerbach) and submucosal (Meissner) plexuses. The myenteric plexus is located between the longitudinal and circular muscle layers of the gut and primarily provides motor innervation to the smooth muscle and secretomotor innervation to the mucosa. The submucosal plexus is located between the circular muscle layer and the muscularis mucosa and primarily innervates the muscularis mucosa, glandular epithelium, intestinal endocrine cells, and submucosal blood vessels. Both plexuses also contain a diverse collection of sensory neurons and interneurons. The complexity of the ENS is demonstrated by expression of over 20 different neuropeptides and neurotransmitters (Crone, 2003 and references therein).

Hirschsprung's disease (HSCR), or congenital aganglionic megacolon, is associated with a lack of intrinsic neurons in the myenteric and submucosal plexuses of the colon, resulting in partial or complete bowel obstruction. This disease affects 1/5000 live births, making it the most common form of congenital bowel obstruction. HSCR disease occurs in both sporadic and familial forms. Human genetic studies reveal that HSCR is a sex-modified multifactorial trait. Mice lacking glial cell line-derived neurotrophic factor (GDNF), the related ligand neurturin, or their receptors c-ret, GFR1alpha, or GFR2alpha lack subsets of enteric neurons. Recent results indicate that RET mutations account for 50% and 15%-20% of familial and sporadic HSCR patients, respectively. Endothelin 3 (EDN-3), endothelin receptor B (ETB), and endothelin converting enzyme-1 mutant mice exhibit aganglionosis of the terminal colon due to premature differentiation of neural crest precursors. Mutations in human EDN-3, ETB, and SOX10 genes are associated with some cases of HSCR. However, a large proportion of HSCR cases cannot be attributed to mutations in known genes, indicating that additional genes may be involved in the etiology of this disease (Crone, 2003 and references therein).

Several lines of evidence suggest that neuregulins and their receptors play a role in the development of the gastrointestinal tract. ErbB2 and erbB3 receptors are expressed in the mucosal epithelia of the colon and small intestine. The NRG-1 ligand is also expressed in the mucosal epithelia as well as in the enteric ganglia. In addition, neuregulin isoforms were shown to alter the morphology of colonic epithelial cells in culture. However, the importance of erbB signaling for the function or maintenance of the ENS has not been investigated (Crone, 2003 and references therein).

ErbB2 null mutants die at embryonic day 10.5 (E10.5) due to a heart defect. In order to examine postnatal roles for erbB2 and to distinguish the different roles erbB2 may play in different cell types, conditional mutants of erbB2 were created in which the erbB2 gene is disrupted only in specific cell types. ErbB2/nestin-Cre mice lack erbB2 expression in the ENS and colonic epithelial cells, whereas erbB2/P0-Cre mice lack erbB2 expression in the ENS. ErbB2/nestin-Cre, but not erbB2/P0-Cre, mutant mice display retarded growth, distended colons, and premature death -- a phenotype that mimics Hirschsprung's (HSCR) disease in humans. Closer examination reveals a loss of enteric neurons and glia in the colon, the diagnostic features of HSCR disease. The loss of enteric neurons and glia occurs postnatally and is due to the loss of erbB2 signaling in the colonic epithelial cells, suggesting a novel mechanism for the manifestation of this phenotype (Crone, 2003).

The maturation of synaptic structures depends on inductive interactions between axons and their prospective targets. One example of such an interaction is the influence of proprioceptive sensory axons on the differentiation of muscle spindles. The expression was monitored of three transcription factors, Egr3, Pea3, and Erm, that delineate early muscle spindle development in an assay of muscle spindle-inducing signals. Genetic evidence shows that Neuregulin1 (Nrg1) is required for proprioceptive afferent-evoked induction of muscle spindle differentiation in the mouse. Ig-Nrg1 isoforms are preferentially expressed by proprioceptive sensory neurons and are sufficient to induce muscle spindle differentiation in vivo, whereas CRD-Nrg1 isoforms are broadly expressed in sensory and motor neurons but are not required for muscle spindle induction (Hippenmeyer, 2002).

Coordinated regulation of neuronal progenitor differentiation in the subventricular zone (SVZ) is a fundamental feature of adult neurogenesis. However, the molecular control of this process remains mostly undeciphered. This study investigated the role of neuregulins (NRGs) in this process and showed that a NRG receptor, ErbB4, is primarily expressed by polysialylated neural cell adhesion molecule immature neuroblasts but is also detected in a subset of GFAP(+) astroglial cells, ependymal cells, and Dlx2(+) precursors in the SVZ. Of the NRG ligands, both NRG-1 and -2 are expressed by immature polysialylated neural cell adhesion molecule neuroblasts in the SVZ. NRG2 is also expressed by some of the GFAP(+) putative stem cells lining the ventricles. Infusion of exogenous NRG1 leads to rapid aggregation of Dlx2(+) cells in the SVZ and affects the initiation and maintenance of organized neuroblast migration from the SVZ toward the olfactory bulb. In contrast, the infusion of NRG2 increased the number of Sox2 and GFAP(+) precursors in the SVZ. An outcome of this NRG2 effect is an increase in the number of newly generated migrating neuroblasts in the rostral migratory stream and GABAergic interneurons in the olfactory bulb. The analysis of conditional null mice that lack NRG receptor, ErbB4, in the nervous system revealed that the observed activities of NRG2 require ErbB4 activation. These results indicate that different NRG ligands affect distinct populations of differentiating neural precursors in the neurogenic regions of the mature forebrain. Furthermore, these studies identify NRG2 as a factor capable of promoting SVZ proliferation, leading to the formation of new neurons in vivo (Ghashghaei, 2006 ).

Radial glial cells play a critical role in the construction of mammalian brain by functioning as a source of new neurons and by providing a scaffold for radial migration of new neurons to their target locations. Radial glia transform into astrocytes at the end of embryonic development. Strategies to promote functional recovery in the injured adult brain depend on the generation of new neurons and the appropriate guidance of these neurons to where they are needed, two critical functions of radial glia. Thus, the competence to regain radial glial identity in the adult brain is of significance for the ability to promote functional repair via neurogenesis and targeted neuronal migration in the mature brain. This study shows that the in vivo induction of the tyrosine kinase receptor, ErbB2, in mature astrocytes enables a subset of them to regain radial glial identity in the mature cerebral cortex. These new radial glial progenitors are capable of giving rise to new neurons and can support neuronal migration. These studies indicate that ErbB2 signaling critically modulates the functional state of radial glia, and induction of ErbB2 in distinct adult astrocytes can promote radial glial identity in the mature cerebral cortex (Ghashghaei, 2007).

Many organs rely on undifferentiated stem and progenitor cells for tissue regeneration. Whether differentiated cells themselves can contribute to cell replacement and tissue regeneration is a controversial question. This study shows that differentiated heart muscle cells, cardiomyocytes, can be induced to proliferate and regenerate. An underlying molecular mechanism was identified for controlling this process that involves the growth factor neuregulin1 (NRG1) and its tyrosine kinase receptor, ErbB4. NRG1 induces mononucleated, but not binucleated, cardiomyocytes to divide. In vivo, genetic inactivation of ErbB4 reduces cardiomyocyte proliferation, whereas increasing ErbB4 expression enhances it. Injecting NRG1 in adult mice induces cardiomyocyte cell-cycle activity and promotes myocardial regeneration, leading to improved function after myocardial infarction. Undifferentiated progenitor cells did not contribute to NRG1-induced cardiomyocyte proliferation. Thus, increasing the activity of the NRG1/ErbB4 signaling pathway may provide a molecular strategy to promote myocardial regeneration (Bersell, 2009).

Neuregulin and neural plasticity

Neu differentiation factor (NDF/neuregulin) is widely expressed in the central and peripheral nervous systems, where it functions as a mediator of the interactions between nerve cells and Schwann, glia, oligodendrocyte, and muscle cells, to control cellular proliferation, differentiation, and migration. NDF binds to two receptor tyrosine kinases, ErbB-3 and ErbB-4. NDF and its ErbB-4 receptor are highly reactive to changes in ambient neuronal activity in the rodent brain in a region-selective manner. Generation of epileptic seizures by using kainic acid, a potent glutamate analog, elevates levels of NDF transcripts in limbic cortical areas, hippocampus, and amygdala. Concomitantly, ErbB-4 mRNA is increased with a similar spatial distribution, but transcription of the other NDF receptor, ErbB-3, does not change. A more moderate stimulation, forced locomotion, is accompanied by an increase in NDF transcripts and protein in the hippocampus and in the motor cortex. Similar changes were found with ErbB-4, but not ErbB-3. Last, a pathway-specific tetanic stimulation of the perforant path, which produces long-term potentiation, is followed by induction of NDF expression in the ipsilateral dentate gyrus and CA3 area of the hippocampus. Taken together, these results indicate that NDF is regulated by physiological activity and may play a role in neural plasticity. One possible function of NDF up-regulation may be to protect brain cells against the excitotoxic effects of glutamate-like molecules (e.g., NMDA). Another function might be a postsynaptic effect on transmission efficacy, similar to the role of ARIA/neuregulin in strengthening neuromuscular synapses. Alternatively, retrograde transport of hippocampal NDF may support survival of forebrain cholinergic neurons (Eilam, 1998).

Neuregulin-1 (NRG1) signaling participates in numerous neurodevelopmental processes. Through linkage analysis, nrg1 has been associated with schizophrenia, although its pathophysiological role is not understood. The prevailing models of schizophrenia invoke hypofunction of the glutamatergic synapse and defects in early development of hippocampal-cortical circuitry. This study shows that the erbB4 receptor, as a postsynaptic target of NRG1, plays a key role in activity-dependent maturation and plasticity of excitatory synaptic structure and function. Synaptic activity leads to the activation and recruitment of erbB4 into the synapse. Overexpressed erbB4 selectively enhances AMPA synaptic currents and increases dendritic spine size. Preventing NRG1/erbB4 signaling destabilizes synaptic AMPA receptors and leads to loss of synaptic NMDA currents and spines. These results indicate that normal activity-driven glutamatergic synapse development is impaired by genetic deficits in NRG1/erbB4 signaling leading to glutamatergic hypofunction. These findings link proposed effectors in schizophrenia: NRG1/erbB4 signaling perturbation, neurodevelopmental deficit, and glutamatergic hypofunction (Li, 2007).

Neuregulin-1 (NRG1), a regulator of neural development, has been shown to regulate neurotransmission at excitatory synapses. Although ErbB4, a key NRG1 receptor, is expressed in glutamic acid decarboxylase (GAD)-positive neurons, little is known about its role in GABAergic transmission. This study shows that ErbB4 is localized at GABAergic terminals of the prefrontal cortex. The data indicate a role of NRG1, both endogenous and exogenous, in regulation of GABAergic transmission. This effect is blocked by inhibition or mutation of ErbB4, suggesting the involvement of ErbB4. Together, these results indicate that NRG1 regulates GABAergic transmission via presynaptic ErbB4 receptors, identifying a novel function of NRG1. Because both NRG1 and ErbB4 have emerged as susceptibility genes of schizophrenia, these observations may suggest a mechanism for abnormal GABAergic neurotransmission in this disorder (Woo, 2007).

Table of contents

vein: Biological Overview | Regulation | Protein Interactions | Developmental Biology | Effects of Mutation | References

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