Rac1 regulates pancreatic islet morphogenesis.
BACKGROUND
Pancreatic 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.


RESULTS
To 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.


CONCLUSIONS
Our 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.
Greiner
Thomas U
TU
Stem Cell and Pancreas Developmental Biology, Stem Cell Center, Lund University, BMC B10, Klinikgatan 26, SE-221 84 Lund, Sweden. thomas.greiner@med.lu.se
Kesavan
Gokul
G
Ståhlberg
Anders
A
Semb
Henrik
H
D000818:Animals; D066259:Betacellulin; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology* / Q000254:growth & development*; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000502:physiology*; D009929:Organ Size; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D066259:Betacellulin; D001786:Blood Glucose; C587852:Btc protein, mouse; C587853:Btc protein, rat; D015820:Cadherins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D066246:ErbB Receptors; D020830:rac1 GTP-Binding Protein