ErbB signaling regulates lineage determination of developing pancreatic islet cells in embryonic organ culture.
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 beta-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-alpha, 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. beta-Cell development was augmented by BTC, whereas the development of somatostatin-expressing delta-cells was stimulated by NRG-4. Both ligands decreased the numbers of glucagon-containing alpha-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 delta-cell development, indicating that this erbB4-ligand is an essential factor for delineation of the somatostatin-producing delta-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 beta-cells. This could be applied in the targeted differentiation of stem cells into insulin-producing cells.
Huotari
Mari-Anne
MA
Biomedicum Helsinki, Program for Developmental and Reproductive Biology and Haartman Institute, University of Helsinki, Helsinki 00014, Finland. mari-anne.pulkkinen@helsinki.fi
Miettinen
Päivi J
PJ
Palgi
Jaan
J
Koivisto
Tarja
T
Ustinov
Jarkko
J
Harari
Daniel
D
Yarden
Yosef
Y
Otonkoski
Timo
T
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D066259:Betacellulin; D002454:Cell Differentiation; D004815:Epidermal Growth Factor / Q000032:analysis / Q000235:genetics / Q000494:pharmacology; D066246:ErbB Receptors / Q000032:analysis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D005865:Gestational Age; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D020880:Neuregulins / Q000032:analysis / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000032:analysis; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000032:analysis / Q000235:genetics / Q000494:pharmacology
D000906:Antibodies; C587851:BTC protein, human; D066259:Betacellulin; C587852:Btc protein, mouse; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D020880:Neuregulins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; C467747:neuregulin-4; D004815:Epidermal Growth Factor; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4