Intraislet SLIT-ROBO signaling is required for beta-cell survival and potentiates insulin secretion.
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.
Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
Yu Hsuan Carol
YH
Yang
Jocelyn E
JE
Manning Fox
Kevin L
KL
Zhang
Patrick E
PE
MacDonald
James D
JD
Johnson
D000199:Actins / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology*; D003920:Diabetes Mellitus / Q000503:physiopathology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011971:Receptors, Immunologic / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D000097905:Roundabout Proteins
D000199:Actins; D001562:Benzimidazoles; D002118:Calcium; D006023:Glycoproteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins; C120566:slit protein, vertebrate; C017807:bisbenzimide ethoxide trihydrochloride
glucose metabolism; intracellular calcium signaling; programmed cell death