Abstract
BackgroundPancreatic islets of Langerhans originate from endocrine progenitors within the pancreatic ductal epithelium. Concomitant with differentiation of these progenitors into hormone-producing cells such cells delaminate, aggregate and migrate away from the ductal epithelium. The cellular and molecular mechanisms regulating islet cell delamination and cell migration are poorly understood. Extensive biochemical and cell biological studies using cultured cells demonstrated that Rac1, a member of the Rho family of small GTPases, acts as a key regulator of cell migration.ResultsTo address the functional role of Rac1 in islet morphogenesis, we generated transgenic mice expressing dominant negative Rac1 under regulation of the Rat Insulin Promoter. Blocking Rac1 function in beta cells inhibited their migration away from the ductal epithelium in vivo. Consistently, transgenic islet cell spreading was compromised in vitro. We also show that the EGF-receptor ligand betacellulin induced actin remodelling and cell spreading in wild-type islets, but not in transgenic islets. Finally, we demonstrate that cell-cell contact E-cadherin increased as a consequence of blocking Rac1 activity.ConclusionOur data support a model where Rac1 signalling controls islet cell migration by modulating E-cadherin-mediated cell-cell adhesion. Furthermore, in vitro experiments show that betacellulin stimulated islet cell spreading and actin remodelling is compromised in transgenic islets, suggesting that betacellulin may act as a regulator of Rac1 activity and islet migration in vivo. Our results further emphasize Rac1 as a key regulator of cell migration and cell adhesion during tissue and organ morphogenesis.
Highlights
Pancreatic islets of Langerhans originate from endocrine progenitors within the pancreatic ductal epithelium
In vitro experiments show that betacellulin stimulated islet cell spreading and actin remodelling is compromised in transgenic islets, suggesting that betacellulin may act as a regulator of Rac1 activity and islet migration in vivo
Results from microarray analysis of E15.5 embryonic pancreas suggest that the closely related Rac2 and Rac3 are expressed to a much lower extent (
Summary
Pancreatic islets of Langerhans originate from endocrine progenitors within the pancreatic ductal epithelium. Concomitant with differentiation of these progenitors into hormoneproducing cells such cells delaminate, aggregate and migrate away from the ductal epithelium. All three major pancreatic cell types, including acinar, ductal and endocrine cells, originate from common Insulin promoter factor (Ipf1)/Pancreatic and duodenal homeobox 1 (Pdx1) -expressing progenitors within the posterior foregut endoderm. These cells evaginate from the foregut endoderm to form the dorsal and ventral pancreatic buds that later fuse to form the proper pancreas. Concomitant with branching morphogenesis, cells of the pancreatic ductal epithelium differentiate into Neurogenin 3 (Ngn3)expressing endocrine precursors through regulation of Notch signalling [3,4]. Inconsistent results, such as Rac being capable of both promoting and inhibiting E-cadherin mediated cell-cell adhesion, make it difficult to extract a clear picture of how Rac regulates E-cadherin function in vivo [22,23]
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