A radial axis defined by semaphorin-to-neuropilin signaling controls pancreatic islet morphogenesis

Abstract

The islets of Langerhans are endocrine organs characteristically dispersed throughout the pancreas. During development, endocrine progenitors delaminate, migrate radially and cluster to form islets. Despite the distinctive distribution of islets, spatially localized signals that control islet morphogenesis have not been discovered. Here, we identify a radial signaling axis that instructs developing islet cells to disperse throughout the pancreas. A screen of pancreatic extracellular signals identified factors that stimulated islet cell development. These included semaphorin 3a, a guidance cue in neural development without known functions in the pancreas. In the fetal pancreas, peripheral mesenchymal cells expressed Sema3a, while central nascent islet cells produced the semaphorin receptor neuropilin 2 (Nrp2). Nrp2 mutant islet cells developed in proper numbers, but had defects in migration and were unresponsive to purified Sema3a. Mutant Nrp2 islets aggregated centrally and failed to disperse radially. Thus, Sema3a-Nrp2 signaling along an unrecognized pancreatic developmental axis constitutes a chemoattractant system essential for generating the hallmark morphogenetic properties of pancreatic islets. Unexpectedly, Sema3a- and Nrp2-mediated control of islet morphogenesis is strikingly homologous to mechanisms that regulate radial neuronal migration and cortical lamination in the developing mammalian brain.

In vivo imaging of emerging endocrine cells reveals a requirement for PI3K-regulated motility in pancreatic islet morphogenesis

“…It remains possible that single-cell directional migration guides new endocrine cells to established islets later during postnatal growth and in adulthood, when the rate of new cell emergence is dramatically reduced ( Ackermann and Gannon, 2007 ). Movement of islets away from the duct may occur through a combination of exocrine tissue expansion and active directional migration ( Pauerstein et al, 2017 ).…”

“…However, owing to the experimentally inaccessible location of the pancreas in humans and most animal models, relatively little is known about the cellular dynamics and molecular mechanisms controlling islet morphogenesis. As single endocrine cells as well as clusters have been identified in pancreatic mesenchyme, islet formation has been postulated to involve cell migration in response to external directional cues ( Cole et al, 2009 ; Puri and Hebrok, 2007 ; Pauerstein et al, 2017 ). However, the finding of islet clusters forming in close proximity to the ductal epithelium ( Bader et al, 2016 ; Kesavan et al, 2014 ; Pan and Wright, 2011 ) suggests that cell interactions at close distances might contribute to islet formation.…”

“…Additional studies showed that blockade of G-protein-coupled receptor (GPCR) signaling resulted in a dispersed islet phenotype in mouse pancreas, and disrupted the clustering of principal islet cells in zebrafish ( Serafimidis et al, 2011 ). In a recent report, Semaphorin signaling from the peripheral mesenchyme was suggested to promote directional movement of islet cells ( Pauerstein et al, 2017 ).…”

Endocrine cell type sorting and mature architecture in the islets of Langerhans require expression of Roundabout receptors in β cells

“…It recently was shown that a double deletion of Robo1 and Robo2 in lung pulmonary neuroendocrine cells (PNECs) results in the loss of PNECs’ clustered architecture 34 . The delamination, migration and aggregation of the islets of Langerhans involve several Robo-related neuronal proteins such as Semaphorin, Ephrin/Eph and N-CAM 35 – 40 , as well as direct signals from the nervous system 41 . Moreover, Robo receptors themselves have been implicated in collective cell movement during organogenesis in various mammalian tissues 42 , 43 .…”

In vivostudies of glucagon secretion by human islets transplanted in mice

“…For islet proliferation analysis and representative images presented in this manuscript, fluorescent micrographs were captured with a 40x objective lens. Images were processed in Image J for islet cell mass quantification and Image-Pro Plus for islet cell proliferation using previously described methods [60][61] .…”