title: Altered pancreatic islet function and morphology in mice lacking the Beta-cell surface protein neuroligin-2.
abstract: Neuroligin-2 is a transmembrane, cell-surface protein originally identified as an inhibitory synapse-associated protein in the central nervous system. Neuroligin-2 is also present on the pancreatic beta-cell surface, and there it engages in transcellular interactions that drive functional maturation of the insulin secretory machinery; these are necessary for normal insulin secretion. The effects of neuroligin-2 deficiency on brain and neuronal function and morphology and on behavior and coordination have been extensively characterized using neuroligin-2 knockout mice. The effects of absent neuroligin-2 expression on islet development and function, however, are unknown. Here, to help test whether neuroligin-2 is necessary for normal islet development, we characterized islet morphology in mice lacking neuroligin-2. To test whether-as predicted by our earlier co-culture studies-absence of neuroligin-2 impairs beta cell function, we compared glucose-stimulated insulin secretion by islets from mutant and wild-type mice. Our results show that while islets from neuroligin-2-deficient mice do not to appear to differ architecturally from wild-type islets, they are smaller, fewer in number, and contain beta cells with lower insulin content. Evaluation of transcript levels suggests that upregulation of neuroligin-1 helps compensate for loss of neuroligin-2. Surprisingly, under both basal and stimulating glucose levels, isolated islets from the knockout mice secreted more of their intracellular insulin content. Rat islets with shRNA-mediated neuroligin-2 knockdown also exhibited increased insulin secretion. Neurexin transcript levels were lower in the knockout mice and, consistent with our prior finding that neurexin is a key constituent of the insulin granule docking machinery, insulin granule docking was reduced. These results indicate that neuroligin-2 is not necessary for the formation of pancreatic islets but that neuroligin-2 influences islet size and number. Neuroligin-2-perhaps through its effects on the expression and/or activity of its binding partner neurexin-promotes insulin granule docking, a known constraint on insulin secretion.
authors.affiliation: Department of Medicine, University of California Irvine, School of Medicine, Irvine, California, United States of America.
authors.forename: Charles
authors.initials: C
authors.lastname: Zhang
authors.forename: Arthur T
authors.initials: AT
authors.lastname: Suckow
authors.forename: Steven D
authors.initials: SD
authors.lastname: Chessler
mesh_terms: D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D007328:Insulin; D009419:Nerve Tissue Proteins; C098003:neuroligin 2