Neuregulin and erbB Receptors Play a Critical Role in Neuronal Migration

Río, Carlos; Rieff, Heather I.; Qi, Peimin; Corfas, Gabriel

doi:10.1016/s0896-6273(00)80346-3

Cited by 357 publications

(276 citation statements)

References 61 publications

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“…NRG-1 is known to modulate neuroepithelial cell proliferation and the reciprocal interactions between migrating cortical neurons and their radial glial guides (17,18,44). In the absence of NRG-1 signaling via erbB2 receptors, radial glial function and development is abnormal.…”

Section: Discussionmentioning

confidence: 99%

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Neuregulin 1–erbB2 signaling is required for the establishment of radial glia and their transformation into astrocytes in cerebral cortex

Schmid

McGrath²,

Berechid

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

191

151

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Radial glial cells and astrocytes function to support the construction and maintenance, respectively, of the cerebral cortex. However, the mechanisms that determine how radial glial cells are established, maintained, and transformed into astrocytes in the cerebral cortex are not well understood. Here, we show that neuregulin-1 (NRG-1) exerts a critical role in the establishment of radial glial cells. Radial glial cell generation is significantly impaired in NRG mutants, and this defect can be rescued by exogenous NRG-1. Down-regulation of expression and activity of erbB2, a member of the NRG-1 receptor complex, leads to the transformation of radial glial cells into astrocytes. Reintroduction of erbB2 transforms astrocytes into radial glia. The activated form of the Notch1 receptor, which promotes the radial glial phenotype, activates the erbB2 promoter in radial glial cells. These results suggest that developmental changes in NRG-1-erbB2 interactions modulate the establishment of radial glia and contribute to their appropriate transformation into astrocytes.R adial glial cells play a critical role in the construction of the mammalian brain by contributing to the formation of neurons and astrocytes and providing an instructive scaffold for neuronal migration (1-7). The establishment of radial glial cells from an undifferentiated sheet of neuroepithelium precedes the generation and migration of neurons in the cerebral cortex. During early stages of corticogenesis, radial glial cells can give rise to neurons (3-5). Subsequent neuronal cell movement in the developing mammalian cerebral cortex occurs mainly along radial glial fibers, although nonpyramidal neurons initially migrate into the cortex in a radial glial-independent manner (1, 2, 4-7).During late stages of corticogenesis, as neurogenesis and migration dwindles, the radial glial scaffolding in the telencephalon is dismantled and transformed into type 1 astrocytes (8-10). Astrocytes contribute to the emergence and maintenance of mature brain circuitry through their function as modulators of neuronal activity (11), neurogenesis (12), and as potential neuronal precursors (13). Neurodevelopmental disorders affecting the development of radial glial cells lead to faulty neuronal and glial differentiation, thus resulting in gross CNS malformations characterized by neuronal misplacement and connectivity (14). Despite their significance, the molecular signals controlling the establishment, maintenance, and transformation of radial glial cells in the developing cerebral cortex are poorly defined.Neuregulin-1 (NRG-1), a member of the NRG family of proteins, has been implicated in the differentiation of glial cells from both central and peripheral nervous systems (15, 16). In the developing CNS, NRG-1 is expressed in migrating neurons and oligodendrocyte precursors and is thought to positively influence radial glial cell function and oligodendrocyte development (17-21). NRG-1 mediates its effects via the activation of dimers of protein tyrosine kinase receptors, erbB2, ...

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Section: Discussionmentioning

confidence: 99%

“…In the developing CNS, NRG-1 is expressed in migrating neurons and oligodendrocyte precursors and is thought to positively influence radial glial cell function and oligodendrocyte development (17)(18)(19)(20)(21). NRG-1 mediates its effects via the activation of dimers of protein tyrosine kinase receptors, erbB2, erbB3, and erbB4.…”

mentioning

confidence: 99%

Neuregulin 1–erbB2 signaling is required for the establishment of radial glia and their transformation into astrocytes in cerebral cortex

Schmid

McGrath²,

Berechid

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

191

151

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“…Types I͞II have also been implicated in the formation of muscle spindles, revealing a role for NRG1 in proprioception (25). NRG has also been shown to affect neuronal migration on radial glial guides in cerebral cortex and cerebellum via ErbB2 and ErbB4 receptors, respectively (26,27). Recently, NRG1 has been identified as a permissive modulator of tangential migration of neurons in the embryonic cortex and the adult RMS (12, 28).…”

mentioning

confidence: 99%

The role of neuregulin–ErbB4 interactions on the proliferation and organization of cells in the subventricular zone

Ghashghaei

Weber

Pevny

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

154

129

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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. Here, we investigate the role of neuregulins (NRGs) in this process and show 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 NRG1 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.adult neurogenesis ͉ rostral migratory stream ͉ schizophrenia T he primary sites of neurogenesis in the adult rodent brain are in the hippocampus and the forebrain subventricular zone [SVZ (1-9)]. The multipotential cells in the SVZ are believed to give rise to a collection of migrating neural progenitors that form the rostral migratory stream (RMS). These cells transit from the anterior SVZ to the olfactory bulb and appear to migrate tangentially along each other through tubes composed of astrocytic-like glial cells (3, 4). Upon their arrival at the posterior core of the olfactory bulb, the cells exit the RMS, switch from a tangential to radial mode of migration, and differentiate into functional granule interneurons or periglomerular interneurons (10, 11).The observation that the receptor tyrosine kinase ErbB4 is selectively expressed at high levels in the SVZ and RMS (12) suggests a possible role for the ErbB4 ligands, the neuregulins (NRGs), as modulators of the proliferation and migration of neural stem and progenitor cells. The NRGs are a collection of related polypeptides characterized by the presence of a single EGF-like domain, capable of binding to and activating ErbB receptors, of which there are four members, ErbB1-4. NRGs serve as ligands for ErbB4 (13) and ErbB3 (14-16) but can be potent activators of ErbB2 and weak activators of the E...

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“…Targeted disruptions of the NRG-1 gene as well as the neuregulin receptors demonstrate that neuregulins are essential for the formation of the heart and nervous system (39,40). Neuregulins have been implicated in a number of events in cell survival, mitosis, migration, and differentiation (41)(42)(43)(44). The survival of Schwann cells, for example, is mediated by neuregulin signaling through the phosphoinositide 3-kinase (PI3K)/Akt pathway, a critical survival pathway in neurons and in most cell types (45).…”

mentioning

confidence: 99%

Cyclin-dependent Kinase-5 Is Involved in Neuregulin-dependent Activation of Phosphatidylinositol 3-Kinase and Akt Activity Mediating Neuronal Survival

Jaffe

et al. 2003

Journal of Biological Chemistry

144

119

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The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays an important role in mediating survival signals in wide variety of neurons and cells. Recent studies show that Akt also regulates metabolic pathways to regulate cell survival. In this study, we reported that cyclin-dependent kinase-5 (Cdk5) regulates Akt activity and cell survival through the neuregulin-mediated PI 3-kinase signaling pathway. We found that brain extracts of Cdk5؊/؊ mice display a lower PI 3-kinase activity and phosphorylation of Akt compared with that in wild type mice. Moreover, we demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. These findings suggest that Cdk5 may exert a key role in promoting neuronal survival by regulating Akt activity through the neuregulin/PI 3-kinase signaling pathway.Cyclin-dependent kinase 5 (Cdk5) 1 is a serine/threonine kinase, which is predominantly expressed in postmitotic neurons (1). Cdk5 kinase activity requires association with its neuronspecific activators, p35 and p39. Cdk5 kinase activity is essential for neuronal migration, neurite outgrowth, and laminar configuration of the cerebral cortex (2-4). Recently, Cdk5 has been suggested as contributing to the control of neuronal positioning in Reelin signaling during neural development (5) and to mediate neuronal guidance by regulating semaphorin-3A with Fyn kinase (6). Cdk5 and p35 have recently also been shown to regulate presynaptic and postsynaptic activity by phosphorylating Munc-18, amphiphysin, and the NR2A subunit of the N-methyl-D-aspartate receptor (7-11). Cdk5 activity also regulates dopamine signaling by phosphorylating DARPP-32 protein (12) and has been shown to up-regulate the expression of acetylcholine receptor at the neuromuscular junction (13). These studies indicate that Cdk5 is a multifunctional protein kinase in the central nervous system. Cdk5 has been implicated in both cell survival and programmed cell death in neuronal and nonneuronal systems (14,15). Cells induced to apoptosis by exogenous signals such as staurosporin display increased Cdk5 activity (16,17). Recently, Cdk5 in association with p25, a truncated form of p35, has been thought to be deregulated to produce hyperphosphorylated tau protein and to disrupt the neuronal cytoskeleton, and it may be involved in neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral secrosis, Parkinson's disease, and Niemann-Pick disease (18 -23). On the other hand, Cdk5 may also be involved in neuronal survival. Cdk5 knockout mice exhibit a unique phenotype with perinatal mortality, associated with extensively disrupted cerebral cortical layering due to abnormal neuronal migration, absence of cerebella foliation, and degeneration of neurons...

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Neuregulin and erbB Receptors Play a Critical Role in Neuronal Migration

Cited by 357 publications

References 61 publications

Neuregulin 1–erbB2 signaling is required for the establishment of radial glia and their transformation into astrocytes in cerebral cortex

Neuregulin 1–erbB2 signaling is required for the establishment of radial glia and their transformation into astrocytes in cerebral cortex

The role of neuregulin–ErbB4 interactions on the proliferation and organization of cells in the subventricular zone

Cyclin-dependent Kinase-5 Is Involved in Neuregulin-dependent Activation of Phosphatidylinositol 3-Kinase and Akt Activity Mediating Neuronal Survival

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