Morphogenesis of the Islets of Langerhans Is Guided by Extraendocrine Slit2 and Slit3 Signals

ABSTRACT

The spatial architecture of the islets of Langerhans is vitally important for their correct function, and alterations in islet morphogenesis often result in diabetes mellitus. We have previously reported that Roundabout (Robo) receptors are required for proper islet morphogenesis. As part of the Slit-Robo signaling pathway, Robo receptors function in conjunction with Slit ligands to mediate axon guidance, cell migration, and cell positioning in development. However, the role of Slit ligands in islet morphogenesis has not yet been determined. Here, we report that Slit ligands are expressed in overlapping and distinct patterns in both endocrine and nonendocrine tissues in late pancreas development. We show that the function of either Slit2 or Slit3, which are predominantly expressed in the pancreatic mesenchyme, is required and sufficient for islet morphogenesis, while Slit1, which is predominantly expressed in the β cells, is dispensable for islet morphogenesis. We further show that Slit functions as a repellent signal to β cells. These data suggest that clustering of endocrine cells during islet morphogenesis is guided, at least in part, by repelling Slit2/3 signals from the pancreatic mesenchyme.

KEYWORDS:

• islets of Langerhans
• pancreas development
• Slit-Robo

View publisher note:

Articles of Significant Interest in This Issue

ACKNOWLEDGMENTS

We thank members of the Blum laboratory, especially Bayley Waters and Dex Nimkulrat, for technical help and valuable discussion and comments on the manuscript. We thank Le Ma, David Ornitz, Alain Chedotal, and Marc Tessier-Lavigne for mice. We are grateful to Francis Lynn and Nicole Krentz for allowing us to use their scRNA-Seq data and to Cody Frederickson for help generating figures. We are also grateful to Lance Rodenkirch and the UW—Madison Optical Imaging Core for help with imaging.

This work was funded in part by R01DK121706 from the NIDDK, the DRC at Washington University Pilot Grant P30DK020579, and Pilot Award UL1TR000427 from the UW—Madison Institute for Clinical and Translational Research (ICTR). J.M.G. and M.T.A. were funded by 5T32GM007133-44, a graduate training award from the UW—Madison Stem Cell & Regenerative Medicine Center, and an Advanced Opportunity Fellowship through SciMed Graduate Research Scholars at UW—Madison.

Conceptualization, B.B. and J.M.G.; Methodology, B.B. and J.M.G.; Investigation, J.M.G., M.T.A., N.S., and H.J.; Formal Analysis, J.M.G., M.T.A., N.S., and H.J.; Writing—Original Draft, B.B. and J.M.G.; Writing, Review, and Editing, all authors; Funding Acquisition, B.B.; Supervision, B.B.