ErbB Signaling Regulates Lineage Determination of Developing Pancreatic Islet Cells in Embryonic Organ Culture

• Published in: Endocrinology (Philadelphia) 2002-11, Vol.143 (11), p.4437-4446
• Main Authors: Huotari, Mari-Anne, Miettinen, Päivi J, Palgi, Jaan, Koivisto, Tarja, Ustinov, Jarkko, Harari, Daniel, Yarden, Yosef, Otonkoski, Timo
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - pharmacology; Beta cells; Betacellulin; Binding; Cell culture; Cell Differentiation; Differentiation (biology); Embryogenesis; Epidermal growth factor; Epidermal Growth Factor - analysis; Epidermal Growth Factor - genetics; Epidermal Growth Factor - pharmacology; ErbB protein; ErbB-1 protein; ErbB-2 protein; ErbB-3 protein; ErbB-4 protein; Fusion protein; Gene Expression; Gestational Age; Glucagon; Growth factors; Heparin; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins - analysis; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - pharmacology; Islet cells; Islets of Langerhans - cytology; Islets of Langerhans - embryology; Kinases; Ligands; Mice; Mice, Knockout; Morphogenesis; Neuregulin; Neuregulins - analysis; Neuregulins - genetics; Neuregulins - immunology; Neuregulins - pharmacology; Neutralization; Organ culture; Organ Culture Techniques; Pancreas; Receptor, Epidermal Growth Factor - analysis; Receptor, Epidermal Growth Factor - deficiency; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - physiology; Receptor, ErbB-4; Receptors; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Signal Transduction; Somatostatin; Stem cells; Transforming Growth Factor alpha - analysis; Transforming Growth Factor alpha - genetics; Transforming Growth Factor alpha - pharmacology; Transforming growth factor-a; Tyrosine
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2002-220382

The neuregulin (NRG)/epidermal growth factor (EGF) family of growth factors consists of several ligands that specifically activate four erbB receptor-tyrosine kinases, namely erbB-1 (EGF-R), erbB-2 (neu), erbB-3, and erbB-4. We have previously shown that islet morphogenesis is impaired and β-cell differentiation delayed in mice lacking functional EGF-R [EGF-R (−/−)]. The present study aims to clarify which erbB ligands are important for islet development. Pancreatic expression of EGF, TGF-α, heparin-binding EGF, betacellulin (BTC), and NRG-4 was detected as early as embryonic d 13 (E13). Effects of these ligands were studied in E12.5 pancreatic explant cultures grown for 5 d ex vivo. None of the growth factors affected the ratio of endocrine to exocrine cells. However, significant effects within the endocrine cell populations were induced by EGF, BTC, and NRG-4. β-Cell development was augmented by BTC, whereas the development of somatostatin-expressing δ-cells was stimulated by NRG-4. Both ligands decreased the numbers of glucagon-containing α-cells. The effect of BTC was abolished in the EGF-R (−/−) mice. A soluble erbB-4 binding fusion protein totally inhibited the effects of NRG-4 but not of BTC. Neutralization of endogenous NRG-4 activity in the model system effectively inhibited δ-cell development, indicating that this erbB4-ligand is an essential factor for delineation of the somatostatin-producing δ-cells. Our results suggest that ligands of the EGF-R/erbB-1 and erbB-4 receptors regulate the lineage determination of islet cells during pancreatic development. BTC, acting through EGF-R/erbB-1, is important for the differentiation of β-cells. This could be applied in the targeted differentiation of stem cells into insulin-producing cells.