Alternative titles; symbols
HGNC Approved Gene Symbol: ERBB4
Cytogenetic location: 2q34 Genomic coordinates (GRCh38): 2:211,375,717-212,538,802 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q34 | Amyotrophic lateral sclerosis 19 | 615515 | Autosomal dominant | 3 |
The HER4/ERBB4 gene is a member of the type I receptor tyrosine kinase subfamily that includes EGFR (131550), ERBB2 (164870), and ERBB3 (190151). It encodes a receptor for NDF/heregulin (NRG1; 142445) (summary by Takahashi et al., 2013).
Using in situ hybridization and immunohistochemical analysis, Srinivasan et al. (1998) showed that Erbb4 was extensively expressed in adult and fetal mouse tissues. Expression was strong in the lining epithelia of the gastrointestinal, urinary, reproductive, and respiratory tracts, as well as in skin, skeletal muscle, circulatory, endocrine, and nervous systems. The developing brain and heart expressed high levels of Erbb4.
Using human cDNA probes in fluorescence in situ hybridization, Zimonjic et al. (1995) mapped the ERBB4 gene to chromosome 2q33.3-q34. The finding established that the ERBB4 gene, like the related EGFR, ERBB2, and ERBB3 genes, is located in close proximity to homeobox and collagen gene loci.
Gross (2013) mapped the ERBB4 gene to chromosome 2q34 based on an alignment of the ERBB4 sequence (GenBank BC112199) with the genomic sequence (GRCh37).
Neuregulins and their receptors, the ERBB protein tyrosine kinases, are essential for neuronal development. Huang et al. (2000) reported that ERBB4 is enriched in the postsynaptic density and associates with PSD95 (602887). Heterologous expression of PSD95 enhanced NRG (142445) activation of ERBB4 and MAP kinase (see 176948). Conversely, inhibiting expression of PSD95 in neurons attenuated NRG-mediated activation of MAP kinase. PSD95 formed a ternary complex with 2 molecules of ERBB4, suggesting that PSD95 facilitates ERBB4 dimerization. Finally, NRG suppressed induction of long-term potentiation in the hippocampal CA1 region without affecting basal synaptic transmission. Thus, NRG signaling may be synaptic and regulated by PSD95. Huang et al. (2000) concluded that a role of NRG signaling in the adult central nervous system may be modulation of synaptic plasticity.
Garcia et al. (2000) found that Erbb4 and Psd95 coimmunoprecipitated from rat forebrain lysates and that the direct interaction was mediated through the C-terminal end of Erbb4. Immunofluorescent studies of cultured rat hippocampal cells showed that Erbb4 colocalized with Psd95 and NMDA receptors at interneuronal postsynaptic sites. The findings suggested that certain ERBB receptors interact with other receptors and may be important in activity-dependent synaptic plasticity.
ERBB4 is a transmembrane receptor tyrosine kinase that regulates cell proliferation and differentiation. After binding its ligand, heregulin, or activation of protein kinase C (see 176960) by TPA, the ERBB4 ectodomain is cleaved by a metalloprotease. Ni et al. (2001) reported a subsequent cleavage by gamma-secretase that releases the ERBB4 intracellular domain from the membrane and facilitates its translocation to the nucleus. Gamma-secretase cleavage was prevented by chemical inhibitors or a dominant-negative presenilin (104311). Inhibition of gamma-secretase also prevented growth inhibition by heregulin. Ni et al. (2001) concluded that gamma-secretase cleavage of ERBB4 may represent another mechanism for receptor tyrosine kinase-mediated signaling.
By immunoprecipitation analysis, Diamonti et al. (2002) showed that NRDP1 (RNF41; 620051) interacted specifically with the ERBB3 and ERBB4 receptors, with the interaction independent of the receptor activation state. When coexpressed in COS7 cells, NRDP1 and ERBB3 colocalized extensively, and NRDP1 expression specifically induced redistribution of ERBB3 from the cell surface to intracellular NRDP1-containing compartments. Further analysis indicated that NRDP1 induced suppression of ERBB3 and ERBB4 receptor levels in COS7 cells. A polypeptide corresponding to the C-terminal 183 amino acids of human NRDP1 interfered with ERBB3 removal and potentiated neuregulin signaling in MCF7 cells by acting as a dominant-negative inhibitor of the NRDP1-mediated process.
Memon et al. (2004) used real-time PCR to quantify expression of NRG1, NRG2 (603818), NRG3 (605533), and NRG4 (610894) and their receptors HER3 and HER4 in biopsies from 88 bladder cancer patients. They detected NRG4 expression in 91% of bladder cancer cases, with significantly lower expression in biopsies of superficial invasive tumors in comparison to superficial tumors, indicating early loss of NRG4 expression during bladder cancer progression. NRG4 downregulation was strongly correlated with stage, grade, and type of tumor. Increased expression of HER3, HER4, and NRG4 correlated to better survival. Coexpression of HER3 and HER4 with NRG4 showed even better correlation with survival (p = 0.0034 and p = 0.0080, respectively).
Using transfected mouse and human cells, Sardi et al. (2006) found that, upon NRG1-induced activation and presenilin-dependent cleavage of ERBB4, the ERBB4 intracellular domain formed a complex with the signaling protein TAB2 (MAP3K7IP2; 605101) and the corepressor NCOR (600849). This complex translocated to the nucleus of undifferentiated rat neural precursors and inhibited their differentiation into astrocytes by repressing transcription of glial genes. Consistent with this observation, cortical astrogenesis occurred precociously in Erbb4-knockout mice, and this phenotype could be rescued by reexpression of a cleavable isoform of human ERBB4, but not by reexpression of an uncleavable ERBB4 isoform.
Lopez-Bendito et al. (2006) found that development of the mouse thalamocortical projection, one of the most prominent tracts in forebrain, depended on early tangential migration of GABAergic neurons from the lateral to the medial ganglionic eminence. This migration was essential to form a permissive corridor for thalamocortical axons (TCAs) to navigate through the telencephalon. Erbb4 and 2 different Nrg1 isoforms, CRD-Nrg1 and Ig-Nrg1, controlled the guidance of TCAs in the telencephalon.
Possible Role in Schizophrenia
Hahn et al. (2006) found that postmortem tissue slices of prefrontal cortex obtained from patients with schizophrenia (181500) demonstrated significantly increased NRG1-induced activation of ERBB4 compared to controls despite similar levels of the 2 proteins. Tissue from schizophrenia subjects also showed increases in ERBB4-PSD95 interactions although this finding was independent of ERBB4 stimulation. NRG1-induced suppression of NMDA receptor (see, e.g., GRIN1; 138249) activation was more pronounced in schizophrenia subjects compared to controls, consistent with enhanced NRG1-ERBB4 signaling. The findings were consistent with the hypothesis that NMDA receptor hypofunction may play a role in schizophrenia. An Editorial Expression of Concern has been published regarding the Western blot images presented in some of the figures in the article by Hahn et al. (2006).
Using human constructs and RNA interference against endogenous rat proteins, Li et al. (2007) demonstrated 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 led to the activation and recruitment of ERBB4 into the synapse. Overexpressed ERBB4 selectively enhanced AMPA synaptic currents and increased dendritic spine size. Preventing NRG1/ERBB4 signaling destabilized synaptic receptors and led to loss of synaptic NMDA currents and spines. Li et al. (2007) concluded that normal activity-driven glutamatergic synapse development is impaired by genetic defects in NRG1/ERBB4 signaling leading to glutaminergic hypofunction. These findings linked proposed effectors in schizophrenia: NRB1/ERBB4 signaling perturbation, neurodevelopmental deficit, and glutamatergic hypofunction.
Woo et al. (2007) showed that Erbb4 localized at GABAergic terminals of rat prefrontal cortex. Studies using the endogenous rodent protein and an exogenous human construct indicated a role for NRG1 in regulation of GABAergic transmission. This effect was blocked by inhibition or mutation of rodent Erbb4, suggesting the involvement of ERBB4. Taken together, the results indicated that NRG1 regulates GABAergic transmission via presynaptic ERBB4 receptors, identifying a novel function of NRG1. Woo et al. (2007) suggested that since both NRG1 and ERBB4 have emerged as susceptibility genes of schizophrenia, these observations may indicate a mechanism for abnormal GABAergic neurotransmission in that disorder.
Fazzari et al. (2010) showed that Nrg1 and ErbB4 signaling controls the development of inhibitory circuitries in the mammalian cerebral cortex by cell-autonomously regulating the connectivity of specific GABA-containing interneurons. In contrast to the view that supports a role for these genes in the formation and function of excitatory synapses between pyramidal cells, Fazzari et al. (2010) found that ErbB4 expression in the mouse neocortex and hippocampus is largely confined to certain classes of interneurons. In particular, ErbB4 is expressed by many parvalbumin (168890)-expressing chandelier and basket cells, where it localizes to axon terminals and postsynaptic densities receiving glutamatergic input. Gain- and loss-of-function experiments, both in vitro and in vivo, demonstrated that ErbB4 cell-autonomously promotes the formation of axo-axonic inhibitory synapses over pyramidal cells, and that this function is probably mediated by Nrg1. In addition, ErbB4 expression in GABA-containing interneurons regulates the formation of excitatory synapses onto the dendrites of these cells. By contrast, ErbB4 is dispensable for excitatory transmission between pyramidal neurons. Fazzari et al. (2010) concluded that Nrg1 and ErbB4 signaling is required for the wiring of GABA-mediated circuits in the postnatal cortex, providing a new perspective to the involvement of these genes in the etiology of schizophrenia.
NMDAR hypofunction is considered a key detrimental consequence of excessive NRG1-ErbB4 signaling found in people with schizophrenia. Using whole cell recordings of mouse hippocampal slices, Pitcher et al. (2011) found that Nrg1-beta-ErbB4 signaling blocked Src (190090) kinase-induced enhancement of NMDAR excitatory currents. However, this signaling pathway did not affect basal NMDAR function. Similar results were observed in pyramidal cells in the prefrontal cortex. Nrg1-beta also prevented long-term potentiation of synaptic transmission induced by theta-burst stimulation. The study identified Src as a downstream target of the Nrg1-beta-ErbB4 signaling pathway and indicated that Src activity is an essential step in regulating synaptic plasticity.
Amyotrophic Lateral Sclerosis 19
In 3 Japanese sibs with late-onset amyotrophic lateral sclerosis-19 (ALS19; 615515), Takahashi et al. (2013) identified a heterozygous missense mutation in the ERBB4 gene (R927Q; 600543.0001). The mutation was found by whole-genome sequencing after exclusion of mutations in several known ALS-associated genes. Sequencing of the ERBB4 gene in 364 familial ALS and 818 sporadic ALS cases identified 1 Canadian individual with familial ALS who also carried the heterozygous R927Q mutation and a Japanese individual with sporadic ALS who carried a different de novo heterozygous missense mutation (R1275W; 600543.0002). The patients with the R927Q mutation had onset of classic upper and lower motor neuron degeneration between 60 and 70 years of age, whereas the patient with the R1275W mutation had earlier onset at age 45. In vitro functional expression studies in COS-7 cells showed that the mutant ERBB4 proteins had decreased autophosphorylation upon NRG1 stimulation compared to wildtype. The findings suggested that disruption of the neuregulin-ERBB4 pathway is involved in the pathogenesis of ALS.
Possible Role in Schizophrenia
Silberberg et al. (2006) identified a linkage disequilibrium block comprising 3 SNPs in exon 3 of the ERBB4 gene (rs707284, rs839523, and rs7598440) that was significantly associated with schizophrenia (181500) in a study of 59 Ashkenazi Jewish patients and 130 controls. The most strongly associated haplotype conferred an odds ratio of 2.18 for development of the disease. Postmortem RT-PCR analysis of 77 human brains showed increased expression of the CYT-1 and JM-a ERBB4 isoforms in schizophrenia compared to controls. Silberberg et al. (2006) concluded that NRG1 and ERBB4 are components of a biologic pathway involved in schizophrenia, perhaps by affecting neuronal migration and resulting in alteration of cortical connectivity.
Possible Role in Melanoma
Prickett et al. (2009) performed a mutational analysis of the protein tyrosine kinase gene family in cutaneous metastatic melanoma (155600). They identified 30 somatic mutations affecting the kinase domains of 19 protein tyrosine kinases and subsequently evaluated the entire coding regions of the genes encoding these 19 protein tyrosine kinases for somatic mutations in 79 melanoma samples. Prickett et al. (2009) found ERBB4 mutations in 19% of individuals with melanoma and found mutations in 2 other kinases (FLT1, 165070 and PTK2B, 601212) in 10% of individuals with melanomas. Prickett et al. (2009) examined 7 missense mutations in ERBB4, and found that they resulted in increased kinase activity and transformation ability. Melanoma cells expressing mutant ERBB4 had reduced cell growth after shRNA-mediated knockdown of ERBB4 or treatment with the ERBB inhibitor lapatinib.
ErbB4 -/- mouse embryos develop trigeminal ganglion and geniculate/cochleovestibular ganglia that are displaced toward each other and show axonal misprojections (Gassmann et al., 1995). Golding et al. (2000) found that these morphologic changes correlate with aberrant migration of a subpopulation of hindbrain-derived cranial neural crest cells. The aberrant migration is also accompanied by an apparent downregulation of HoxB2 (142967) gene expression. Through transplantation experiments, Golding et al. (2000) determined that neural crest cells deviated from their normal pathway only when transplanted into mutant embryos, suggesting that ErbB4 signaling within the host environment provides patterning information essential for the proper migration of neural crest cells.
Chen et al. (2003) generated transgenic mice that expressed a dominant-negative ErbB4 receptor specifically in nonmyelinating Schwann cells. The mutant mice developed a progressive peripheral neuropathy characterized by extensive Schwann cell proliferation and death, loss of unmyelinated axons, and marked hot and cold pain insensitivity. At later stages, the mutant mice showed a loss of C-fiber dorsal root ganglion neurons. The findings indicated that the NRG1-ErbB4 signaling system contributes to reciprocal interactions between unmyelinated sensory axons and nonmyelinating Schwann cells that appear to be critical for Schwann cell and C-fiber sensory neuron survival.
Anton et al. (2004) found that ERBB4 was expressed at high levels in neural precursor cells in the rat subventricular zone (SVZ) and rostral migratory system (RMS) that are destined to become olfactory interneurons. ERBB4 was also detected in a subset of glial cells. Mice with targeted deletion of the ErbB4 gene in the CNS showed cellular disorganization of the SVZ and RMS as well as altered distribution and differentiation of olfactory interneurons. In vivo, cells explanted from mutant mice failed to form migratory neuronal chains and showed impaired orientation compared to wildtype cells. Anton et al. (2004) concluded that ERBB4 plays a role in RMS neuroblast tangential migration and olfactory interneuronal placement.
Flames et al. (2004) found that mice lacking neural Erbb4 expression had reduced numbers of GABA-positive neurons in the postnatal cortex and hippocampus. They determined that Nrg1 is a neural guidance molecule for GABAergic interneurons from the medial ganglionic eminence. Thus, Flames et al. (2004) attributed the loss of GABAergic neurons in Erbb4 mutant mice to abnormal migration of these interneurons to the neocortex.
Escher et al. (2005) demonstrated that neuromuscular junctions (NMJs) can form in the absence of the neuregulin receptors ErbB2 (164870) and ErbB4 in mouse muscle. Postsynaptic differentiation was, however, induced by agrin (103320). Escher et al. (2005) therefore concluded that neuregulin signaling to muscle is not required for NMJ formation. The effects of neuregulin signaling to muscle may be mediated indirectly through Schwann cells.
In 3 Japanese sibs with late-onset amyotrophic lateral sclerosis-19 (ALS19; 615515), Takahashi et al. (2013) identified a heterozygous c.2780G-A transition in the ERBB4 gene, resulting in an arg927-to-gln (R927Q) substitution at a highly conserved residue in the tyrosine kinase domain. The mutation was found by whole-genome sequencing after exclusion of mutations in several known ALS-associated genes and was consistent with linkage analysis. The mutation was not present in the 1000 Genomes Project or NHLBI Exome Sequencing Project databases or in an in-house database containing 41 whole genomes and 1,408 exomes in the Japanese population. It was also not found in 477 Japanese controls. Sequencing of the ERBB4 gene in 364 familial ALS and 818 sporadic ALS cases identified 1 Canadian individual with familial ALS who also carried the heterozygous R927Q mutation. The mutation was not present in 190 Canadian controls; however, familial segregation analysis was not possible. Haplotype analysis showed that the families shared different haplotypes, arguing against a founder effect. In vitro functional expression studies in COS-7 cells showed that the mutant ERBB4 protein had decreased autophosphorylation upon NRG1 stimulation compared to wildtype. The patients with the R927Q mutation had onset of classic upper and lower motor neuron degeneration between 60 and 70 years of age.
In a Japanese individual with sporadic ALS19 (615515), Takahashi et al. (2013) identified a de novo heterozygous c.3823C-T transition in the ERBB4 gene, resulting in an arg1275-to-trp (R1275W) substitution at a highly conserved residue in a C-terminal domain in the vicinity of multiple phosphorylation sites that mediate downstream signaling pathways. The mutation was not present in the 1000 Genomes Project or NHLBI Sequencing Project databases or in an in-house database containing 41 whole genomes and 1,408 exomes in the Japanese population. It was also not found in 477 Japanese controls. This patient was ascertained from a large cohort of 364 familial ALS and 818 sporadic ALS cases in whom the ERBB4 was sequenced. In vitro functional expression studies in COS-7 cells showed that the mutant ERBB4 protein had decreased autophosphorylation upon NRG1 stimulation compared to wildtype. The patient had onset of classic upper and lower motor neuron degeneration at about 45 years of age.
Anton, E. S., Ghashghaei, H. T., Weber, J. L., McCann, C., Fischer, T. M., Cheung, I. D., Gassmann, M., Messing, A., Klein, R., Schwab, M. H., Lloyd, K. C. K., Lai, C. Receptor tyrosine kinase ErbB4 modulates neuroblast migration and placement in the adult forebrain. Nature Neurosci. 7: 1319-1328, 2004. [PubMed: 15543145] [Full Text: https://doi.org/10.1038/nn1345]
Chen, S., Rio, C., Ji, R.-R., Dikkes, P., Coggeshall, R. E., Woolf, C. J., Corfas, G. Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss. Nature Neurosci. 6: 1186-1193, 2003. [PubMed: 14555954] [Full Text: https://doi.org/10.1038/nn1139]
Diamonti, A. J., Guy, P. M., Ivanof, C., Wong, K., Sweeney, C., Carraway, K. L. An RBCC protein implicated in maintenance of steady-state neuregulin receptor levels. Proc. Nat. Acad. Sci. 99: 2866-2871, 2002. [PubMed: 11867753] [Full Text: https://doi.org/10.1073/pnas.052709799]
Escher, P., Lacazette, E., Courtet, M., Blindenbacher, A., Landmann, L., Bezakova, G., Lloyd, K. C., Mueller, U., Brenner, H. R. Synapses form in skeletal muscles lacking neuregulin receptors. Science 308: 1920-1923, 2005. [PubMed: 15976301] [Full Text: https://doi.org/10.1126/science.1108258]
Fazzari, P., Paternain, A. V., Valiente, M., Pla, R., Lujan, R., Lloyd, K., Lerma, J., Marin, O., Rico, B. Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature 464: 1376-1380, 2010. [PubMed: 20393464] [Full Text: https://doi.org/10.1038/nature08928]
Flames, N., Long, J. E., Garratt, A. N., Fischer, T. M., Gassmann, M., Birchmeier, C., Lai, C., Rubenstein, J. L. R., Marin, O. Short- and long-range attraction of cortical GABAergic interneurons by neuregulin-1. Neuron 44: 251-261, 2004. [PubMed: 15473965] [Full Text: https://doi.org/10.1016/j.neuron.2004.09.028]
Garcia, R. A. G., Vasudevan, K., Buonanno, A. The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses. Proc. Nat. Acad. Sci. 97: 3596-3601, 2000. [PubMed: 10725395] [Full Text: https://doi.org/10.1073/pnas.97.7.3596]
Gassmann, M., Casagranda, F., Orioli, D., Simon, H., Lai, C., Klein, R., Lemke, G. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378: 390-394, 1995. [PubMed: 7477376] [Full Text: https://doi.org/10.1038/378390a0]
Golding, J. P., Trainor, P., Krumlauf, R., Gassmann, M. Defects in pathfinding by cranial neural crest cells in mice lacking the neuregulin receptor ErbB4. Nature Cell Biol. 2: 103-109, 2000. [PubMed: 10655590] [Full Text: https://doi.org/10.1038/35000058]
Gross, M. B. Personal Communication. Baltimore, Md. 11/6/2013.
Hahn, C.-G., Wang, H.-Y., Cho, D.-S., Talbot, K., Gur, R. E., Berrettini, W. H., Bakshi, K., Kamins, J., Borgmann-Winter, K. E., Siegel, S. J., Gallop, R. J., Arnold, S. E. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nature Med. 12: 824-828, 2006. Note: Editorial Expression of Concern. Nature Med. 19Dec, 2023. Advance Electronic Publication. [PubMed: 16767099] [Full Text: https://doi.org/10.1038/nm1418]
Huang, Y. Z., Won, S., Ali, D. W., Wang, Q., Tanowitz, M., Du, Q. S., Pelkey, K. A., Yang, D. J., Xiong, W. C., Salter, M. W., Mei, L. Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses. Neuron 26: 443-455, 2000. [PubMed: 10839362] [Full Text: https://doi.org/10.1016/s0896-6273(00)81176-9]
Li, B., Woo, R.-S., Mei, L., Malinow, R. The neuregulin-1 receptor ErbB4 controls glutamatergic synapse maturation and plasticity. Neuron 54: 583-597, 2007. [PubMed: 17521571] [Full Text: https://doi.org/10.1016/j.neuron.2007.03.028]
Lopez-Bendito, G., Cautinat, A., Sanchez, J. A., Bielle, F., Flames, N., Garratt, A. N., Talmage, D. A., Role, L. W., Charnay, P., Marin, O., Garel, S. Tangential neuronal migration controls axon guidance: a role for neuregulin-1 in thalamocortical axon navigation. Cell 125: 127-142, 2006. [PubMed: 16615895] [Full Text: https://doi.org/10.1016/j.cell.2006.01.042]
Memon, A. A., Sorensen, B. S., Melgard, P., Fokdal, L., Thykjaer, T., Nexo, E. Expression of HER3, HER4 and their ligand heregulin-4 is associated with better survival in bladder cancer patients. Brit. J. Cancer 91: 2034-2041, 2004. [PubMed: 15583696] [Full Text: https://doi.org/10.1038/sj.bjc.6602251]
Ni, C.-Y., Murphy, M. P., Golde, T. E., Carpenter, G. Gamma-secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294: 2179-2181, 2001. [PubMed: 11679632] [Full Text: https://doi.org/10.1126/science.1065412]
Pitcher, G. M., Kalia, L. V., Ng, D., Goodfellow, N. M., Yee, K. T., Lambe, E. K., Salter, M. W. Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors. Nature Med. 17: 470-478, 2011. [PubMed: 21441918] [Full Text: https://doi.org/10.1038/nm.2315]
Prickett, T. D., Agrawal, N. S., Wei, X., Yates, K. E., Lin, J. C., Wunderlich, J. R., Cronin, J. C., Cruz, P., NISC Comparative Sequencing Program, Rosenberg, S. A., Samuels, Y. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nature Genet. 41: 1127-1132, 2009. [PubMed: 19718025] [Full Text: https://doi.org/10.1038/ng.438]
Sardi, S. P., Murtie, J., Koirala, S., Patten, B. A., Corfas, G. Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain. Cell 127: 185-197, 2006. [PubMed: 17018285] [Full Text: https://doi.org/10.1016/j.cell.2006.07.037]
Silberberg, G., Darvasi, A., Pinkas-Kramarski, R., Navon, R. The involvement of ErbB4 with schizophrenia: association and expression studies. Am. J. Med. Genet. 141B: 142-148, 2006. [PubMed: 16402353] [Full Text: https://doi.org/10.1002/ajmg.b.30275]
Srinivasan, R., Poulsom, R., Hurst, H. C., Gullick, W. J. Expression of the c-erbB-4/HER4 protein and mRNA in normal human fetal and adult tissues and in a survey of nine solid tumour types. J. Path. 185: 236-245, 1998. [PubMed: 9771476] [Full Text: https://doi.org/10.1002/(SICI)1096-9896(199807)185:3<236::AID-PATH118>3.0.CO;2-7]
Takahashi, Y., Fukuda, Y., Yoshimura, J., Toyoda, A., Kurppa, K., Moritoyo, H., Belzil, V. V., Dion, P. A., Higasa, K., Doi, K., Ishiura, H., Mitsuli, J., and 28 others. ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19. Am. J. Hum. Genet. 93: 900-905, 2013. [PubMed: 24119685] [Full Text: https://doi.org/10.1016/j.ajhg.2013.09.008]
Woo, R.-S., Li, X.-M., Tao, Y., Carpenter-Hyland, E., Huang, Y. Z., Weber, J., Neiswender, H., Dong, X.-P., Wu, J., Gassmann, M., Lai, C., Xiong, W.-C., Gao, T.-M., Mei, L. Neuregulin-1 enhances depolarization-induced GABA release. Neuron 54: 599-610, 2007. [PubMed: 17521572] [Full Text: https://doi.org/10.1016/j.neuron.2007.04.009]
Zimonjic, D. B., Alimandi, M., Miki, T., Popescu, N. C., Kraus, M. H. Localization of the human HER4/erbB-4 gene to chromosome 2. Oncogene 10: 1235-1237, 1995. [PubMed: 7700649]