Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system

Marchionni, Mark A.; Goodearl, Andrew; Chen, Maio Su; Bermingham‐McDonogh, Olivia; Kirk, Cassandra; Hendricks, Michael; Danehy, Frank; Misumi, Don J; Sudhalter, Judith; Kobayashi, Kihei; Wroblewski, Diana; Lynch, Catherine; Baldassare, Mark; Hiles, Ian D.; Davis, John B.; Hsuan, J. Justin; Totty, Nicholas F.; Otsu, Masayuki; McBurney, Robert N.; Waterfield, Michael D.; Stroobant, Paul; Gwynne, David I.

doi:10.1038/362312a0

Cited by 717 publications

(529 citation statements)

References 46 publications

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“…8,[10][11][12] NRG1 is a very long 1.4 Mb gene with a large number of structurally and functionally distinct isoforms produced by alternative splicing. 13,14 In addition to the genetic evidence, the known biological functions of the protein products of NRG1 agree strongly with it being a schizophrenia susceptibility gene: they play a central role in neural development, are most likely involved in the regulation of synaptic plasticity, that is, basically how the brain responds or adapts to the environment (in keeping with the genes-environment interaction theory of schizophre-nia). 13,[15][16][17][18] NRG1 is also involved in the glutamatergic pathway; the involvement of this system in schizophrenia development is one of the most prominent neurochemical hypothesis proposed to explain the biological component of this disease.…”

Section: Introductionmentioning

confidence: 70%

Extreme population differences across Neuregulin 1 gene, with implications for association studies

et al. 2005

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Neuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia in recent years since its first association with the disease in an Icelandic population. Since then, many association studies have analysed allele and haplotype frequencies in distinct populations yielding varying results: some have replicated the association, although with different alleles or haplotypes being associated, whereas others have failed to replicate the association. These contradictory results might be attributed to population differences in allele and haplotype frequencies. In order to approach this issue, we have typed 13 SNPs across this large 1.4 Mb gene, including two of the SNPs originally found associated with schizophrenia in the Icelandic population, the objective being to discover if the underlying cause of the association discrepancies to date may be due to population-specific genetic variation. The analyses have been performed in a total of 1088 individuals from 39 populations, covering most of the genetic diversity in the human species. Most of the SNPs analysed displayed differing frequencies according to geographical region. These allele differences are especially relevant in two SNPs located in a large intron of the gene, as shown by the extreme F ST values, which reveal genetic stratification correlated to broad continental areas. This finding may be indicative of the influence of some local selective forces on this gene. Furthermore, haplotype analysis reveals a clear clustering according to geographical areas. In summary, our findings suggest that NRG1 presents extreme population differences in allele and haplotype frequencies. We have given recommendations for taking this into account in future association studies since this diversity could give rise to erroneous results.

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Section: Introductionmentioning

confidence: 70%

Extreme population differences across Neuregulin 1 gene, with implications for association studies

et al. 2005

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“…Human epiregulin and EGF were radioiodinated using the lactoperoxidase (LPO) method (Marchalonis, 1969) with a slight modi®cation. Brie¯y, epiregulin or EGF (2 nmol in 5 ml of water) and 25 ml of 0.5 M sodium phosphate, pH 7.5, were added to 1 mg/ml of LPO (Boehringer Mannheim, Germany).…”

Section: Labeling Of Recombinant Human Epiregulin and Egfmentioning

confidence: 99%

“…The other group, neuregulins, is comprised of alternative spliced isoforms from a single gene. The group includes neu di erentiation factor (NDF) (Wen et al, 1992)/heregulin (HRG) (Homes et al, 1992), acetylcholine receptor-inducing activity (Falls et al, 1993) and glial growth factor (Marchionni et al, 1993). These ligands do not interact directly with EGFR and ErbB-2 but bind with low a nity to ErbB-3 and high a nity to ErbB-4 (Plowman et al, 1993b;.…”

Section: Introductionmentioning

confidence: 99%

Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tryosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4

et al. 1997

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Epiregulin is a member of the epidermal growth factor (EGF) family, and has certain characteristics that are di erent from that of EGF, including mitogenic responses and binding to EGF receptor (EGFR). Epiregulin may also have another cell surface receptor and/or induces di erent receptor heterodimerizations for intracellular signaling. We investigated the binding ability of epiregulin to four ErbB family receptors using four human breast carcinoma cell lines that expressed di erent subsets of receptors. Chemical cross-linking experiments showed that [ 125 I]epiregulin directly bound to each of EGFR and ErbB-4 but not to ErbB-2 and ErbB-3. Furthermore, although epiregulin stimulated tyrosine phosphorylation of all four ErbB receptors, the main intracellular signal was mediated by ErbB-4 and/or EGFR. The pattern of activation of ErbB family receptors was di erent from that of other EGF-related ligands. Our ®ndings indicate that ErbB-4 and EGFR are receptors for epiregulin, and suggest that EGFrelated ligands transduce signals for di erent biological responses by the hierarchical mechanism.

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“…NDF, the ligand of ErbB-3 and ErbB-4, is predominantly expressed in the central and peripheral nervous systems, but it is also expressed in other organs, such as the adrenal gland, liver and intestine (Marchionni et al, 1993;Orr-Urtreger et al, 1993;Chen et al, 1994;Birchmeier, 1994, 1995;Pinkas-Kramarski et al, 1994;Corfas et al, 1995;Ho et al, 1995). It has been previously shown by using Northern blot analysis, that the two NDF receptors are widely expressed in various epithelial cell lines (Prigent et al, 1992;Plowman et al, 1993).…”

Section: Erential Expression Of Ndf Receptors In Mouse Developmentmentioning

confidence: 99%

“…A strong mitogenic activity on Schwann cells enabled isolation of the glial growth factors (GGFs) (Marchionni et al, 1993), whereas the ability of another neuregulin isoform to elevate expression of the nicotinic acetylcholine receptor in muscle cells was utilized in isolating ARIA (Falls et al, 1993). The availability of recombinant forms of NDF/neuregulin opened the way for more detailed in vitro and in vivo studies, collectively characterizing two major groups of biological roles for NDFs/neuregulins.…”

Section: Introductionmentioning

confidence: 99%

Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation

et al. 1997

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Two receptor tyrosine kinases, ErB-3 and ErbB-4, mediate signaling by Neu di erentiation factors (NDFs, also called neuregulins), while ErbB-1 and ErbB-2 serve as co-receptors. We show that the two NDF/neuregulin receptors di er in spatial and temporal expression patterns: The kinase-defective receptor, ErbB-3, is expressed primarily in epithelial layers of various organs, in the peripheral nervous system, and in adult brain, whereas ErbB-4 is restricted to the developing central nervous system and to the embryonic heart. An example of alternating expression of the two receptors is provided by the developing cerebellum: During postnatal cerebellar development, ErbB-4 expression slightly decreases along with a decline in NDF transcription, whereas ErbB-3 expression commences after the peak of neurogenesis. To study functional di erences, we established primary brain cultures and found that ErbB-3 was expressed only in oligodendrocytes, whereas ErbB-4 expression was shared by oligodendrocytes, astrocytes and neurons. Blocking the action of endogenous NDF in vitro, by using a soluble form of ErbB-4, accelerated neurite outgrowth in both primary cultures and in neuronal-type cultures of the P19 teratocarcinoma, suggesting an inhibitory e ect of NDF on neural di erentiation. Apparently, ErbB-3 is associated with proliferation of P19 cells, whereas ErbB-4 correlates with a di erentiated phenotype. We conclude that the two NDF receptors play distinct, rather than redundant, developmental and physiological roles.

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Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system

Cited by 717 publications

References 46 publications

Extreme population differences across Neuregulin 1 gene, with implications for association studies

Extreme population differences across Neuregulin 1 gene, with implications for association studies

Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tryosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4

Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation

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