Neural Cell Adhesion Molecule (N-CAM) Is Required for Cell Type Segregation and Normal Ultrastructure in Pancreatic Islets

Abstract

Classical cell dissociation/reaggregation experiments with embryonic tissue and cultured cells have established that cellular cohesiveness, mediated by cell adhesion molecules, is important in determining the organization of cells within tissue and organs. We have employed N-CAM-deficient mice to determine whether N-CAM plays a functional role in the proper segregation of cells during the development of islets of Langerhans. In N-CAM-deficient mice the normal localization of glucagon-producing α cells in the periphery of pancreatic islets is lost, resulting in a more randomized cell distribution. In contrast to the expected reduction of cell–cell adhesion in N-CAM-deficient mice, a significant increase in the clustering of cadherins, F-actin, and cell–cell junctions is observed suggesting enhanced cadherin-mediated adhesion in the absence of proper N-CAM function. These data together with the polarized distribution of islet cell nuclei and Na+/K+-ATPase indicate that islet cell polarity is also affected. Finally, degranulation of β cells suggests that N-CAM is required for normal turnover of insulin-containing secretory granules. Taken together, our results confirm in vivo the hypothesis that a cell adhesion molecule, in this case N-CAM, is required for cell type segregation during organogenesis. Possible mechanisms underlying this phenomenon may include changes in cadherin-mediated adhesion and cell polarity.

IL-1β-induced pro-apoptotic signalling is facilitated by NCAM/FGF receptor signalling and inhibited by the C3d ligand in the INS-1E rat beta cell line

“…This suggests that Ca 2+ -independent cell adhesion molecules such as NCAM are not the primary adhesion molecules in beta cells. In contrast, NCAM regulates cell type segregation during the development of the islets of Langerhans, an effect that is thought to be caused by an NCAM inhibition of cadherin clustering [26,43]. Studies in NCAM-deficient tumour beta cells suggest that NCAM is involved in cell matrix adhesion through β 1 -integrin activation, as part of an FGFR/N-cadherin signalling complex, and loss of NCAM has been implicated in tumour metastasis [27,32].…”

“…Transformed beta cell lines have been reported to express mainly NCAM-140 and in some studies also NCAM-180 though to a minor degree [7,[25][26][27][28][29]. It is unclear which NCAM isoforms are expressed in primary beta cells.…”

“…In some studies mainly the NCAM-140 isoform is reported [7,25,28,29] whereas others report that mainly NCAM-120 is expressed in adult islets and expression of NCAM-140 is found only during development and in tumours [26,27]. In beta cells, NCAM has been suggested to be involved in the organisation of biosociology in the islets of Langerhans [26], in beta cell functional activity measured as insulin release [30], and also in natural killer T cell-induced beta cell death [31]. Furthermore, in mouse pancreatic tumour beta cells, NCAM has been shown to activate a Src-kinase and to bind and activate FGFR [32].…”

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

“…Reorganization of pancreatic islet architecture can result from cell transdifferentiation, altered proliferation, survival, or migration related to remodeled cell-cell contacts (27,67). Transdifferentiation is unlikely to confound our experiments because both α and β cells retained their lineage identities as suggested by the selective presence of Pdx1 and MafA transcription factors in β cells, and glucagon expression restricted to α cells (27,68).…”

“…We propose that increased E-cadherin expression in α cells dispersed in islet cores is for the ectopic anchoring of resident β cells (67), and allows in trans signaling for coordinated hormone secretion. Our E-cadherin data also support the hypothesis that active cell migration participates in mixed islet configuration (67). As such, CB 1 R activation by both eCBs and synthetic agonists promotes the long-distance migration of neuroblasts and endothelial cells (29,30).…”