β1 integrin/FAK/ERK signalling pathway is essential for human fetal islet cell differentiation and survival

β1 integrin and collagen matrix interactions regulate the survival of cells by associating with focal adhesion kinase (FAK) and initiating MAPK/ERK signalling, but little is known about these signalling pathways during human fetal islet ontogeny. The purpose of this study was to investigate whether β1 integrin/FAK activation of the MAPK/ERK pathway regulates human fetal islet cell expression of endocrine cell markers and survival. Isolated human (18–21 weeks fetal age) islet–epithelial cell clusters, cultured on collagen I, were examined using β1 integrin blocking antibody, β1 integrin siRNA and FAK expression vector. Perturbing β1 integrin function in the human fetal islet–epithelial cell clusters resulted in a marked decrease in cell adhesion, in parallel with a reduction in the number of cells expressing PDX-1, insulin and glucagon (p < 0.05). β1 integrin blockade disorganized focal adhesion contacts in the PDX-1+ cells and decreased activation of FAK and ERK1/2 signalling in parallel with an increase in expression of cleaved caspases 9 and 3 (p < 0.01). Similar results were obtained following an siRNA knock-down of β1 integrin expression. In contrast, over-expression of FAK not only increased phospho-ERK and the expression of PDX-1, insulin and glucagon (p < 0.05) but also abrogated the decreases in phospho-ERK and PDX-1 by β1 integrin blockade. This study demonstrates that activation of the FAK/ERK signalling cascade by β1 integrin is involved in the differentiation and survival of human fetal pancreatic islet cells. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.