Cdc42/N-WASP signaling links actin dynamics to pancreatic β cell delamination and differentiation.
Delamination plays a pivotal role during normal development and cancer. Previous work has demonstrated that delamination and epithelial cell movement within the plane of an epithelium are associated with a change in cellular phenotype. However, how this positional change is linked to differentiation remains unknown. Using the developing mouse pancreas as a model system, we show that β cell delamination and differentiation are two independent events, which are controlled by Cdc42/N-WASP signaling. Specifically, we show that expression of constitutively active Cdc42 in β cells inhibits β cell delamination and differentiation. These processes are normally associated with junctional actin and cell-cell junction disassembly and the expression of fate-determining transcription factors, such as Isl1 and MafA. Mechanistically, we demonstrate that genetic ablation of N-WASP in β cells expressing constitutively active Cdc42 partially restores both delamination and β cell differentiation. These findings elucidate how junctional actin dynamics via Cdc42/N-WASP signaling cell-autonomously control not only epithelial delamination but also cell differentiation during mammalian organogenesis.
Stem Cell Center, Department of Laboratory Medicine, Lund University, BMC B10 Klinikgatan 26, SE-22184 Lund, Sweden.
Gokul
G
Kesavan
Oliver
O
Lieven
Anant
A
Mamidi
Zarah Löf
ZL
Öhlin
Jenny Kristina
JK
Johansson
Wan-Chun
WC
Li
Silvia
S
Lommel
Thomas Uwe
TU
Greiner
Henrik
H
Semb
D000199:Actins / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D007365:Intercellular Junctions / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051381:Rats; D015398:Signal Transduction; D059008:Time-Lapse Imaging; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
D000199:Actins; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D020764:cdc42 GTP-Binding Protein
Beta cell delamination; Cdc42; Differentiation