Morphogenesis of the islets of Langerhans is guided by extra-endocrine Slit2/3 signals

Abstract

13The spatial architecture of the islets of Langerhans is vitally important for their correct function, and 14 alterations in islet morphogenesis often result in diabetes mellitus. We have previously reported that 15 function of Roundabout (Robo) receptors, selectively in β-cells, is required for proper islet 16 morphogenesis. As part of the Slit-Robo signaling pathway, Robo receptors work in conjunction with 17 Slit ligands to mediate axon guidance, cell migration, and cell positioning in development. However, 18 the role of Slit ligands in islet morphogenesis has not yet been determined. Here we report that Slit 19 ligands are expressed in overlapping and distinct patterns in both endocrine and non-endocrine tissues 20 in late pancreas development. We show that function of either Slit2 or Slit3, which are predominantly 21 expressed in the pancreatic mesenchyme, is required and sufficient for islet morphogenesis, while 22 Slit1, which is predominantly expressed in the endocrine compartment, is dispensable for islet 23 morphogenesis. We further provide evidence to suggest that Slit-Robo signaling in the pancreas 24 influences endocrine cell-cell adhesion, not cell migration, during islet morphogenesis. These data add 25 important understanding to the fundamental question of the formation of the unique architecture of 26 the islets of Langerhans. 27Alteration of islet cell populations in spontaneously diabetic mice. Diabetes 27, 1-7.

Coordination between ECM and cell-cell adhesion regulates the development of islet aggregation, architecture, and functional maturation

“…The secreted ligand, Slit, is often associated with the ECM, and binds to Robo receptors to control various cellular responses via cytoplasmic kinases and the regulation of actin and microtubule cytoskeleton ( Jiang et al, 2022 ; Tong et al, 2019 ). Mice lacking Robo1 and Robo2 in all endocrine cells, or selectively in β-cells, show complete loss of endocrine cell type sorting in the islets ( Adams et al, 2021 ; Adams et al, 2018 ; Gilbert et al, 2020 ). Interestingly, Robo1/2 DKO islets exhibit adhesion defects and are prone to dissociate upon isolation ( Adams et al, 2018 ), similar to the Ctnna1 ΔEndo/ΔEndo islets.…”

Coordination between ECM and cell-cell adhesion regulates the development of islet aggregation, architecture, and functional maturation

“…The secreted ligand, Slit, is often associated with ECM, and binds to Robo receptors to control various cellular responses via cytoplasmic kinases and regulation of actin and microtubule cytoskeleton (Jiang et al, 2022; Tong et al, 2019). Mice lacking Robo1 and Robo2 in all endocrine cells, or selectively in β cells, show complete loss of endocrine cell type sorting in the islets (Adams et al, 2021; Adams et al, 2018; Gilbert et al, 2020). Interestingly, Robo1/2 double knockout islets exhibit adhesion defects and are prone to dissociate upon isolation (Adams et al, 2018), similar to the Ctnna1 ΔEndo/ΔEndo islets.…”

“…Jiang et al, 2022;Tong et al, 2019). Mice lacking Robo1 and Robo2 in all endocrine cells, or selectively in β cells, show complete loss of endocrine cell type sorting in the islets(Adams et al, 2021;Adams et al, 2018;Gilbert et al, 2020). Interestingly, Robo1/2 double knockout islets exhibit adhesion defects and are prone to dissociate upon isolation(Adams et al, 2018), similar to the Ctnna1 ΔEndo/ΔEndo islets.…”

Islet architecture in adult mice is actively maintained by Robo2 expression in β cells

“…shown to impact islet formation in developing mice (Gilbert et al, 2020). Slit from the pancreatic mesenchyme during development may thus interact with Robo on the developing β cell to direct endocrine cell type sorting (Waters and Blum, 2022).…”