RFX6 Regulates Insulin Secretion by Modulating Ca2+ Homeostasis in Human β Cells

Vikash Chandra 1 Olivier Albagli-Curiel 1 Benoit Hastoy 2 Julie Piccand 3 Clotilde Randriamampita 1 Emmanuel Vaillant 4, 5 Hélène Cavé 6 Kanetee Busiah 7, 1 Philippe Froguel 1, 8 Martine Vaxillaire 4, 5 Patrik Rorsman 2 Michel Polak 1, 7 Raphael Scharfmann 1
1 UM3 (UMR 8104 / U1016) - Institut Cochin
2 Oxford Centre for Diabetes, Endocrinology and Metabolism
3 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
4 Institut Pasteur de Lille
5 EGID - Génomique Intégrative et Modélisation des Maladies Métaboliques
6 Service de génétique [Robert Debré]
7 CHU Necker - Enfants Malades [AP-HP]
8 Department of Genomics of Common Disease
Abstract : Development and function of pancreatic β cells involve the regulated activity of specific transcription factors. RFX6 is a transcription factor essential for mouse β cell differentiation that is mutated in monogenic forms of neonatal diabetes. However, the expression and functional roles of RFX6 in human β cells, especially in pathophysiological conditions, are poorly explored. We demonstrate the presence of RFX6 in adult human pancreatic endocrine cells. Using the recently developed human β cell line EndoC-βH2, we show that RFX6 regulates insulin gene transcription, insulin content, and secretion. Knockdown of RFX6 causes downregulation of Ca2+-channel genes resulting in the reduction in L-type Ca2+-channel activity that leads to suppression of depolarization-evoked insulin exocytosis. We also describe a previously unreported homozygous missense RFX6 mutation (p.V506G) that is associated with neonatal diabetes, which lacks the capacity to activate the insulin promoter and to increase Ca2+-channel expression. Our data therefore provide insights for understanding certain forms of neonatal diabetes.
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Cell Biology International Reports, Wiley Open Access, 2014, 9 (6), pp.2206-2218. 〈10.1016/j.celrep.2014.11.010〉
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Vikash Chandra, Olivier Albagli-Curiel, Benoit Hastoy, Julie Piccand, Clotilde Randriamampita, et al.. RFX6 Regulates Insulin Secretion by Modulating Ca2+ Homeostasis in Human β Cells. Cell Biology International Reports, Wiley Open Access, 2014, 9 (6), pp.2206-2218. 〈10.1016/j.celrep.2014.11.010〉. 〈inserm-01103648〉

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