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题名:Intraislet SLIT-ROBO signaling is required for beta-cell survival and potentiates insulin secretion.
作者:YANG YH; MANNING FOX JE; ZHANG KL; MACDONALD PE; JOHNSON JD;
来源:Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16480-5. doi: [ IF= 0.00 ] ]
URL :10.1073/pnas.1214312110
日期:20131104
摘要:We previously cataloged putative autocrine/paracrine signaling loops in
pancreatic islets, including factors best known for their roles in axon guidance.
Emerging evidence points to nonneuronal roles for these factors, including the
Slit-Roundabout receptor (Robo) family, in cell growth, migration, and survival.
We found SLIT1 and SLIT3 in both beta cells and alpha cells, whereas SLIT2 was
predominantly expressed in beta cells. ROBO1 and ROBO2 receptors were detected in
beta and alpha cells. Remarkably, even modest knockdown of Slit production
resulted in significant beta-cell death, demonstrating a critical
autocrine/paracrine survival role for this pathway. Indeed, recombinant SLIT1,
SLIT2, and SLIT3 decreased serum deprivation, cytokine, and thapsigargin-induced
cell death under hyperglycemic conditions. SLIT treatment also induced a gradual
release of endoplasmic reticulum luminal Ca(2+), suggesting a unique molecular
mechanism capable of protecting beta cells from endoplasmic reticulum
stress-induced apoptosis. SLIT treatment was also associated with rapid actin
remodeling. SLITs potentiated glucose-stimulated insulin secretion and increased
the frequency of glucose-induced Ca(2+) oscillations. These observations point to
unexpected roles for local Slit secretion in the survival and function of
pancreatic beta cells. Because diabetes results from a deficiency in functional
beta-cell mass, these studies may contribute to therapeutic approaches for
improving beta-cell survival and function.

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