Molecular basis for the regulation of islet beta cell mass in mice: the role of E-cadherin.
OBJECTIVE
In rodents and humans, the rate of beta cell proliferation declines rapidly after birth; formation of the islets of Langerhans begins perinatally and continues after birth. Here, we tested the hypothesis that increasing levels of E-cadherin during islet formation mediate the decline in beta cell proliferation rate by contributing to a reduction of nuclear β-catenin and D-cyclins.


METHODS
We examined E-cadherin, nuclear β-catenin, and D-cyclin levels, as well as cell proliferation during in vitro and in vivo formation of islet cell aggregates, using β-TC6 cells and transgenic mice with green fluorescent protein (GFP)-labelled beta cells, respectively. We tested the role of E-cadherin using antisense-mediated reductions of E-cadherin in β-TC6 cells, and mice segregating for a beta cell-specific E-cadherin knockout (Ecad [also known as Cdh1] βKO).


RESULTS
In vitro, pseudo-islets of β-TC6 cells displayed increased E-cadherin but decreased nuclear β-catenin and cyclin D2, and reduced rates of cell proliferation, compared with monolayers. Antisense knockdown of E-cadherin increased cell proliferation and levels of cyclins D1 and D2. After birth, beta cells showed increased levels of E-cadherin, but decreased levels of D-cyclin, whereas islets of Ecad βKO mice showed increased levels of D-cyclins and nuclear β-catenin, as well as increased beta cell proliferation. These islets were significantly larger than those of control mice and displayed reduced levels of connexin 36. These changes correlated with reduced insulin response to ambient glucose, both in vitro and in vivo.


CONCLUSIONS
The findings support our hypothesis by indicating an important role of E-cadherin in the control of beta cell mass and function.
Department of Pediatrics, Columbia University, New York, NY, USA.
N
N
Wakae-Takada
S
S
Xuan
K
K
Watanabe
P
P
Meda
R L
RL
Leibel
D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D049109:Cell Proliferation; D056741:Cyclin D / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016376:Oligonucleotides, Antisense / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
D015820:Cadherins; D056741:Cyclin D; D016376:Oligonucleotides, Antisense; D051176:beta Catenin; D049452:Green Fluorescent Proteins; D005947:Glucose