Netrin-1 expression in fetal and regenerating rat pancreas and its effect on the migration of human pancreatic duct and porcine islet precursor cells

Abstract

Aims/hypothesis. We investigated the expression and function of netrin-1, a diffusible laminin-like protein known to regulate neuronal-cell migration in the pancreas. We questioned whether this factor regulates migration of pancreatic epithelial cells and whether this could be involved in islet neogenesis. Methods. We studied fetal and adult rat pancreas wherein duct ligation induced islet neogenesis. Netrin-1 expression was analysed by RT-PCR, western blot and immunohistochemistry. In vitro cell migration was measured with a human pancreatic duct cell line (CAPAN-2) and with fetal porcine islet cells. We also studied the expression of two netrin-receptors, neogenin and deleted in colorectal cancer. Results. We found a transient expression of netrin-1 mRNA and protein in fetal pancreas from E15 to E18, and in adult pancreas after duct ligation. In normal adult pancreas there was very little netrin-1 expression. Netrin-1 expression was observed both in endocrine and exocrine cells. At the immunohistochemical level, it was expressed by islet cells during tissue regeneration. We could show that netrin-1 increases the migration of fetal islet cells and of a ductal cell line, mainly via a chemokinetic effect. From the two wellestablished netrin receptors, DCC and neogenin, we only found neogenin to be expressed in the pancreas. Neogenin expression coincided with the period of netrin-1 up-regulation. Conclusion/interpretation. Netrin-1 is involved in pancreatic morphogenesis and tissue remodelling and plays a role in the regulation of duct-cell and fetalislet cell migration. This can be of importance in islet regeneration, where migration of islet precursors takes place. [Diabetologia (2003) 46:926-933]

Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signalling via dependence receptors

“…Actions of netrins outside of neuronal development have been described in mammary gland and lung branching morphogenesis [21,24,35,36]. Netrins have been ascribed a role in pancreatic development [21,23,24], but were previously undetected in adult islet cells in the absence of injury [23,24]. Three secreted netrins (netrin-1, -3, -4) and the two glucose-6-phosphate isomerase-anchored sub-classes (netrin-G1, netrin-G2) were identified via bioinformatics and genomics in mouse and human islets (Fig.…”

“…Given the many parallels between development and cell fate decisions in neurons and the endocrine pancreas, we focused on the netrin family and their receptors. In multiple tissues, including the developing pancreas, netrins have been implicated as regulators of cell adhesion, migration, differentiation and organ morphogenesis [21,23,24]. They regulate apoptosis via their dependence receptors [25][26][27] and downstream signalling pathways involving v-akt murine thymoma viral oncogene homologue (Akt), extracellular signal-regulated protein kinase (ERK) and apoptosis signal-regulating kinase 1 (ASK1) [21,25,26,28].…”

“…They regulate apoptosis via their dependence receptors [25][26][27] and downstream signalling pathways involving v-akt murine thymoma viral oncogene homologue (Akt), extracellular signal-regulated protein kinase (ERK) and apoptosis signal-regulating kinase 1 (ASK1) [21,25,26,28]. Although it has been previously reported that netrin-1 expression is undetectable in adult pancreatic islet cells in the absence of tissue remodelling [23,24], we show that multiple netrin proteins are present in adult beta cells, where they modulate caspase-3 activity in a context-dependent manner through the neogenin and unc-5 homologue (UNC5) A dependence receptors. Together, our genome-level findings point to a large number of potentially important local paracrine growth factor loops in pancreatic islets.…”

CD40 expression on human pancreatic duct cells: role in nuclear factor-kappa B activation and production of pro-inflammatory cytokines

“…Cell cultures Human adenocarcinoma cell line (Capan-2) was kindly provided by Dr L. Bouwens (Cell Differentiation Unit, Brussels Free University, Belgium) and was cultured as previously described [30]. Briefly, cells were cultured in McCoy's 5A medium with glutamax-1 (Invitrogen, Merelbeke, Belgium) supplemented with 50 U/ml penicillin, 50 µg/ml streptomycin (BioWhittaker, Verviers, Belgium) and 10% FCS (Hyclone, Erembodegem, Belgium).…”

Axon guidance factor netrin-1 and its receptors regulate angiogenesis after cerebral ischemia

“…Netrin-1 was the first to be purified and is the best-characterized member. In addition to its involvement in guiding axon migration during embryonic development, netrin-1 functions in organ formation [3][4][5][6] , tumorigenesis [7] , inflammation [8,9] , and anti-apoptotis [10] , as well as being a potential biomarker for renal injury and certain cancers [11,12] . It also promotes the recovery of neuronal function after cerebral ischemia in animal models [13][14][15][16] .…”