Neurohypophyseal Neuregulin 1 Is Derived from the Hypothalamus as a Potential Prolactin Modulator

Abstract

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.

Neuregulin 4 (Nrg4) cooperates with melatonin to regulate the PRL expression via ErbB4/Erk signaling pathway as a potential prolactin (PRL) regulator

“…These processes were accompanied by promotion in expression and secretion of PRL, which Erk inhibitor and siRNA targeting Nrg4 can suppress this process. Although a previous study has indicated the significance of the PI3K-Akt cascade in initiating PRL promoter activity, 34,35 our study found that Nrg4 concentrations below 10 nM were unable to induce phosphorylated Akt activation. Similar to Nrg1, the Erk signal is involved in the regulation of PRL expression by Nrg4.…”

Neuregulins in Neurodegenerative Diseases

“…The results of a growing number of studies suggest that NRG1 regulates cell maintenance, differentiation, proliferation, migration, and survival or apoptosis in both neuronal and nonneuronal cell types (Mei and Xiong, 2008). Research on NRGs and their corresponding receptors in both invertebrate and vertebrate models, including Drosophila (Hidalgo et al, 2001), zebrafish (Brown et al, 2017), mouse (Kato et al, 2009), rat (Zhao et al, 2015) and even non-human primate rhesus monkey (Zhao, 2013b), have shown their complex involvement in the development of the nervous system and related diseases.…”

Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer

“…The NRG1 gene is located on the 8p12 region of the short arm of chromosome 8; it can translate to six different NRG1 (neuregulin1) protein types and over 30 different isoforms that act as extracellular EGF-like ligands for ERBB3/HER3 and ERRB4/HER41; the many different isoforms may be the reason why NRG1 can influence diverse functions such as proliferation and differentiation of glial, neuronal, and Schwann cells, expression of acetylcholine receptors in synaptic vesicles during neuromuscular junction formation, growth of skeletal muscle cells, lobuloalveolar budding/milk production in the breast, differentiation of breast cancer cells, and the development of the myocardium [ 4 ]. Neurohypophyseal NRG1 is derived from the hypothalamus as a prolactin modulator and is mainly expressed in rat pituitary gonadotrope cells and possibly regulates prolactin secretion in a juxtacrine manner [ 5 , 6 ].…”