Altered neuregulin 1–erbB4 signaling contributes to NMDA> receptor hypofunction in schizophrenia
Chang-Gyu HahnHoau-Yan WangDan-Sung ChoKonrad TalbotRaquel E. GurWade H. BerrettiniKalindi BakshiJoshua KaminsKarin E. Borgmann‐WinterSteven J. SiegelRobert GallopSteven E. Arnold
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Understanding the control of myelin formation by oligodendrocytes is essential for treating demyelinating diseases. Neuregulin-1 (NRG1) type III, an EGF-like growth factor, is essential for myelination in the PNS. It is thus thought that NRG1/ErbB signaling also regulates CNS myelination, a view suggested by in vitro studies and the overexpression of dominant-negative ErbB receptors. To directly test this hypothesis, we generated a series of conditional null mutants that completely lack NRG1 beginning at different stages of neural development. Unexpectedly, these mice assemble normal amounts of myelin. In addition, double mutants lacking oligodendroglial ErbB3 and ErbB4 become myelinated in the absence of any stimulation by neuregulins. In contrast, a significant hypermyelination is achieved by transgenic overexpression of NRG1 type I or NRG1 type III. Thus, NRG1/ErbB signaling is markedly different between Schwann cells and oligodendrocytes that have evolved an NRG/ErbB-independent mechanism of myelination control.
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Neuregulin-1 (NRG1), known also as heregulin, acetylcholine receptor inducing activity (ARIA), glial growth factor (GGF), or sensory and motor neuron derived factor (SMDF), plays essential roles in several developmental processes, and is required also later in life. Many variants of NRG1 are produced via alternative splicing and usage of distinct promoters. All contain an epidermal growth factor (EGF)-like domain, which alone is sufficient to bind and activate the cognate receptors, members of the ErbB family. NRG1 mediated signaling is crucial for cardiogenesis and the development of the mammary gland and ErbB2 (HER2), an orphan co-receptor for NRG1 is the target of the drug Herceptin® (trastuzumab) used for treatment of metastatic breast cancer. In the nervous system, NRG1 controls the early development of subpopulations of neural crest cells. In particular, NRG1 acts as an essential paracrine signaling molecule expressed on the axonal surface, where it signals to Schwann cells throughout development and regulates the thickness of the myelin sheath. NRG1 is required also by other cell types in the nervous system, for instance as an axonal signal released by proprioceptive afferents to induce development of the muscle spindle, and it controls aspects of cortical interneuron development as well as the formation of thalamocortical projections. Work from several laboratories implicates dysregulation of NRG1/ErbB4 signaling in the etiology of schizophrenia. Biochemical studies have shown that the precursor proteins of NRG1 can be released from the membrane through limited proteolysis. In addition, most NRG1 isoforms contain a transmembrane domain, which is processed by γ-secretase after shedding. Thereby the intracellular domain is released into the cytoplasm. Despite this, the importance of NRG1 cleavage for its functions in vivo remained unclear until recently. β- Secretase (β-site amyloid precursor protein cleaving enzyme 1, BACE1) was first identified through its function as the rate limiting enzyme of amyloid-β-peptide (Aβ) production. Aβ is the major component of amyloid plaques in Alzheimers disease (AD). More recently it was shown that Neuregulin-1 is a major physiological substrate of BACE1 during early postnatal development. Mutant mice lacking BACE1 display severe hypomyelination of peripheral nerves similar to that seen in mice lacking NRG1/ErbB signaling in Schwann cells, and a BACE1-dependent activation of NRG1 in the process of peripheral myelination was proposed. Here we summarize the current knowledge about the role of NRG1 proteolysis for ErbB receptor mediated signaling during development and in Alzheimers disease. Keywords: Alzheimer's disease, A,APP, BACE1, neuregulin, schizophrenia, secretase, heparin-binding, CRD-Neuregulin, proteolytic activation
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ラット褐色細胞腫 (PC12細胞) からRT-PCR法を用いてErbB新規リガンドとそのアイソフォーム4種類を同定し, 成熟ラットの脳と胸腺で強く発現していることから neural- and thymus-derived activator for ErbB kinases (NTAK) と命名した. 予想される蛋白質構造は免疫グロブリン (Ig) 様ドメイン, EGF様ドメイン, 疎水性ドメインからなりEGFファミリーのメンバーである neuregulin-1 (NRG-1) と同様のドメイン構造を示した. 哺乳動物細胞発現系を用いてこの蛋白質を精製したところ46kDaの糖蛋白質で, ヒト乳癌細胞株MDA-MB-453細胞を分化させた. NTAKはホモダイマーのErbB3, ErbB4には結合するがErbB1とErbB2には結合しなかった. しかし, これらのレセプターをヘテロダイマーで細胞表面上に発現させると, 構成する全てのレセプターでチロシンのリン酸化が観察された. このことは, NTAKが結合すると異なるErbBファミリーが二量体を形成し, 活性化してクロストークすることを示唆している. よって, NTAKは新しいEGFファミリーのメンバーでNRG-1様の機能を持っていることが明らかになった.
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Objectives: Neuregulin-1 (NRG-1) is a cardioactive paracrine growth factor released by microvascular endothelial cells, which has shown cardioprotective effects in animal models of heart failure. ErbB4 is a member of the ErbB family that serve as receptor for NRG-1. Administration of NRG-1 has been shown to improve LV function in chronic heart failure (CHF) experimental models. Our aim was to determine whether CHF is associated with changes in expression and distribution of NRG-1 and its receptor erbB4 in human myocardium.
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