EGFR signalling controls cellular fate and pancreatic organogenesis by regulating apicobasal polarity

TY - JOUR

T1 - EGFR signalling controls cellular fate and pancreatic organogenesis by regulating apicobasal polarity

AU - Löf-Öhlin, Zarah M

AU - Nyeng, Pia

AU - Bechard, Matthew E

AU - Hess, Katja

AU - Bankaitis, Eric

AU - Greiner, Thomas U

AU - Ameri, Jacqueline

AU - Wright, Christopher V

AU - Semb, Henrik

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Apicobasal polarity is known to affect epithelial morphogenesis and cell differentiation, but it remains unknown how these processes are mechanistically orchestrated. We find that ligand-specific EGFR signalling via PI(3)K and Rac1 autonomously modulates apicobasal polarity to enforce the sequential control of morphogenesis and cell differentiation. Initially, EGF controls pancreatic tubulogenesis by negatively regulating apical polarity induction. Subsequently, betacellulin, working via inhibition of atypical protein kinase C (aPKC), causes apical domain constriction within neurogenin3+endocrine progenitors, which results in reduced Notch signalling, increased neurogenin3 expression, and β-cell differentiation. Notably, the ligand-specific EGFR output is not driven at the ligand level, but seems to have evolved in response to stage-specific epithelial influences. The EGFR-mediated control of β-cell differentiation via apical polarity is also conserved in human neurogenin3+cells. We provide insight into how ligand-specific EGFR signalling coordinates epithelial morphogenesis and cell differentiation via apical polarity dynamics.

AB - Apicobasal polarity is known to affect epithelial morphogenesis and cell differentiation, but it remains unknown how these processes are mechanistically orchestrated. We find that ligand-specific EGFR signalling via PI(3)K and Rac1 autonomously modulates apicobasal polarity to enforce the sequential control of morphogenesis and cell differentiation. Initially, EGF controls pancreatic tubulogenesis by negatively regulating apical polarity induction. Subsequently, betacellulin, working via inhibition of atypical protein kinase C (aPKC), causes apical domain constriction within neurogenin3+endocrine progenitors, which results in reduced Notch signalling, increased neurogenin3 expression, and β-cell differentiation. Notably, the ligand-specific EGFR output is not driven at the ligand level, but seems to have evolved in response to stage-specific epithelial influences. The EGFR-mediated control of β-cell differentiation via apical polarity is also conserved in human neurogenin3+cells. We provide insight into how ligand-specific EGFR signalling coordinates epithelial morphogenesis and cell differentiation via apical polarity dynamics.

KW - Animals

KW - Basic Helix-Loop-Helix Transcription Factors/metabolism

KW - Cell Differentiation/physiology

KW - Cell Polarity/physiology

KW - Epithelial Cells/metabolism

KW - Insulin-Secreting Cells/metabolism

KW - Mice

KW - Mice, Knockout

KW - Morphogenesis/physiology

KW - Nerve Tissue Proteins/metabolism

KW - Neuropeptides/metabolism

KW - Organogenesis/physiology

KW - Phosphatidylinositol 3-Kinases/metabolism

KW - Protein Kinase C/metabolism

KW - Receptor, Epidermal Growth Factor/metabolism

KW - Signal Transduction/physiology

KW - rac1 GTP-Binding Protein/metabolism

U2 - 10.1038/ncb3628

DO - 10.1038/ncb3628

M3 - Journal article

C2 - 29058721

SN - 1465-7392

VL - 19

SP - 1313

EP - 1325

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 11

ER -