Although neuregulin 1 (Nrg1) has been identified in the rat hypothalamus, the localisation of Nrg1 in the hypothalamus-hypophyseal structure and its functions remain unclear and require further elucidation. In this study, we identified the existence of Nrg1β types I-III in the rat hypothalamus. We demonstrated that Nrg1 was partially localised in somatostatin-positive cells in the periventricular nucleus. It was also co-localised with arginine vasopressin in the supraoptic nucleus, median eminence and pituitary stalk. Nrg1 was also extensively distributed in the posterior pituitary (PP), including the projected neuronal fibres that surround the vascular structure and Herring bodies. Western blotting confirmed that these signals were primarily produced by soluble Nrg1 derived from a 45-kDa Nrg1 precursor mainly identified in the hypothalamus. Similar to Nrg1α, Nrg1β increased the prolactin (PRL) expression in rat pituitary RC-4B/C cells, which can be inhibited by an Akt inhibitor. In addition, Nrg1β had no apparent effect on growth hormone expression at the mRNA or protein levels. Collectively, we conclude that hypothalamic Nrg1 may be transported to the PP as the β form. We further hypothesise that Nrg1β may function via the regulation of PRL expression through a paracrine mechanism.

1.
Orr-Urtreger A, Trakhtenbrot L, Ben-Levy R, Wen D, Rechavi G, Lonai P, Yarden Y: Neural expression and chromosomal mapping of Neu differentiation factor to 8p12-p21. Proc Natl Acad Sci USA 1993;90:1867-1871.
2.
Mei L, Nave KA: Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases. Neuron 2014;83:27-49.
3.
Rosnack KJ, Stroh JG, Singleton DH, Guarino BC, Andrews GC: Use of capillary electrophoresis-electrospray ionization mass spectrometry in the analysis of synthetic peptides. J Chromatogr A 1994;675:219-225.
4.
Jacobsen NE, Abadi N, Sliwkowski MX, Reilly D, Skelton NJ, Fairbrother WJ: High-resolution solution structure of the EGF-like domain of heregulin-α. Biochemistry 1996;35:3402-3417.
5.
Bao J, Wolpowitz D, Role LW, Talmage DA: Back signaling by the Nrg-1 intracellular domain. J Cell Biol 2003;161:1133-1141.
6.
Hancock ML, Canetta SE, Role LW, Talmage DA: Presynaptic type III neuregulin1-ErbB signaling targets α7 nicotinic acetylcholine receptors to axons. J Cell Biol 2008;181:511-521.
7.
Liu J, Kern JA: Nrg1 activates the JAK-STAT pathway and regulates lung epithelial cell proliferation. Am J Respir Cell Mol Biol 2002;27:306-313.
8.
Hahn CG, Wang HY, Cho DS, Talbot K, Gur RE, Berrettini WH, Bakshi K, Kamins J, Borgmann-Winter KE, Siegel SJ, Gallop RJ, Arnold SE: Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 2006;12:824-828.
9.
Peles ER, Ben-Levy E, Tzahar E, Liu N, Wen D, Yarden Y: Cell-type specific interaction of Neu differentiation factor (NDF/heregulin) with Neu/HER-2 suggests complex ligand-receptor relationships. EMBO J 1993;12:961-971.
10.
Puricelli L, Proietti CJ, Labriola L, Salatino M, Balañá ME, Aguirre Ghiso J, Lupu R, Pignataro OP, Charreau EH, Bal de Kier Joffé E, Elizalde PV: Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells. Int J Cancer 2002;100:642-653.
11.
Bernstein HG, Lendeckel U, Bertram I, Bukowska A, Kanakis D, Dobrowolny H, Stauch R, Krell D, Mawrin C, Budinger E, Keilhoff G, Bogerts B: Localization of Nrg1α (heregulin-α) and one of its receptors, ErbB4 tyrosine kinase, in developing and adult human brain. Brain Res Bull 2006;69:546-559.
12.
Snodgrass-Belt P, Gilbert JL, Davis FC: Central administration of transforming growth factor-α and Nrg1 suppress active behaviors and cause weight loss in hamsters. Brain Res 2005;1038:171-182.
13.
Ojeda SR, Ma YJ: Glial-neuronal interactions in the neuroendocrine control of mammalian puberty: facilitatory effects of gonadal steroids. J Neurobiol 1999;40:528-540.
14.
Prevot V, Rio C, Cho GJ, Lomniczi A, Heger S, Neville CM, Rosenthal NA, Ojeda SR, Corfas G: Normal female sexual development requires neuregulin-erbB receptor signaling in hypothalamic astrocytes. J Neurosci 2003;23:230-239.
15.
Sharif A, Duhem-Tonnelle V, Allet C, Baroncini M, Loyens A, Kerr-Conte J, Collier F, Blond S, Ojeda SR, Junier MP, Prevot V: Differential erbB signaling in astrocytes from the cerebral cortex and the hypothalamus of the human brain. Glia 2009;57:362-379.
16.
Taylor SB, Taylor AR, Markham JA, Geurts AM, Kanaskie BZ, Koenig JI: Disruption of the neuregulin 1 gene in the rat alters HPA axis activity and behavioral responses to environmental stimuli. Physiol Behav 2011:104:205-214.
17.
Steinmetz R, Gutierrez-Hartmann A, Bigsby RM, Ben-Jonathan N: Activation of the prolactin promoter in transfected GH3 cells by posterior pituitary cells. Endocrinology 1994;135:2737-2741.
18.
Vlotides G, Cooper O, Chen YH, Ren SG, Greenland Y, Melmed S: Heregulin regulates prolactinoma gene expression. Cancer Res 2009;69:4209-4216.
19.
Zhao W, Ren SG: Neuregulin-1 (Nrg1) is mainly expressed in rat pituitary gonadotroph cells and possibly regulates prolactin (PRL) secretion in a juxtacrine manner. J Neuroendocrinol 2011;23:1252-1262.
20.
Zhao WJ, Ren SG: Endogenous neuregulin-1 expression in the anterior pituitary of female Wistar-Furth rats during the estrous cycle (in Chinese). Nan Fang Yi Ke Da Xue Xue Bao 2011;32:921-927.
21.
Zhao W, Shen Y, Ren S: Endogenous expression of neuregulin-1 (Nrg1) as a potential modulator of prolactin (PRL) secretion in GH3 cells. Cell Tissue Res 2011;344:313-320.
22.
Cote GM, Miller TA, Lebrasseur NK, Kuramochi Y, Sawyer DB: Nrg1α and β isoform expression in cardiac microvascular endothelial cells and function in cardiac myocytes in vitro. Exp Cell Res 2005;311:135-146.
23.
Borrelli E, Sawchenko PE, Evans RM: Pituitary hyperplasia induced by ectopic expression of nerve growth factor. Proc Natl Acad Sci USA 1992;89:2764-2768.
24.
Cai A, Hayes JD, Patel N, Hyde JF: Targeted overexpression of galanin in lactotrophs of transgenic mice induces hyperprolactinemia. Endocrinology 1999;140:4955-4964.
25.
Spuch C, Diz-Chaves Y: Fibroblast growth factor-2 and epidermal growth factor modulate prolactin responses to TRH and dopamine in primary cultures. Endocrine 2006;29:317-324.
26.
Desikan V, Roque C, Wilson TA: Does pituitary stalk function improve with age? J Pediatr Endocrinol Metab 2009;22:859-862.
27.
Iacovazzo D, Lugli F, Giampietro A: Ectopic posterior pituitary causing hyperprolactinemia. Endocrine 2012;42:449-450.
28.
Murakami T, Miyake T, Ohtsuka A, Kikuta A, Taguchi T: Microcirculatory patterns in adult rat cerebral hypophysis: a scanning electron microscope study of replicated specimens. Arch Histol Cytol 1993;56:243-260.
29.
Murakami T, Ohtsuka A, Taguchi T, Kikuta A, Ohtani O: Blood vascular bed of the rat pituitary intermediate lobe, with special reference to its development and portal drainage into the anterior lobe. A scanning electron microscope study of vascular casts. Arch Histol Jpn 1985;48:69-87.
30.
László FA, Varga C, Pávó I, Gardi J, Vecsernyés M, Gálfi M, Morschl E, László F, Makara GB: Vasopressin pressor receptor-mediated activation of HPA axis by acute ethanol stress in rats. Am J Physiol Regul Integr Comp Physiol 2001;280:R458-R465.
31.
Hayakawa J, Ohmichi M, Tasaka K, Kanda Y, Adachi K, Nishio Y, Hisamoto K, Mabuchi S, Hinuma S, Murata Y: Regulation of the PRL promoter by Akt through cAMP response element binding protein. Endocrinology 2002;143:13-22.
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