During pancreas development endocrine cells leave the ductal epithelium to form the islets of Langerhans, but the morphogenetic mechanisms are incompletely understood. Here, we identify the Ca2+-independent atypical Synaptotagmin-13 (Syt13) as a key regulator of endocrine cell egression and islet formation. We detect specific upregulation of the Syt13 gene and encoded protein in endocrine precursors and the respective lineage during islet formation. The Syt13 protein is localized to the apical membrane of endocrine precursors and to the front domain of egressing endocrine cells, marking a previously unidentified apical-basal to front-rear repolarization during endocrine precursor cell egression. Knockout of Syt13 impairs endocrine cell egression and skews the α-to-β-cell ratio. Mechanistically, Syt13 is a vesicle trafficking protein, transported via the microtubule cytoskeleton, and interacts with phosphatidylinositol phospholipids for polarized localization. By internalizing a subset of plasma membrane proteins at the front domain, including α6β4 integrins, Syt13 modulates cell-matrix adhesion and allows efficient endocrine cell egression. Altogether, these findings uncover an unexpected role for Syt13 as a morphogenetic driver of endocrinogenesis and islet formation.

Center of Membrane Biochemistry and Lipid Research Carl Gustav Carus School of Medicine Technische Universität Dresden Dresden Germany

German Center for Diabetes Research Neuherberg Germany

Institute for Ophthalmic Research Center for Ophthalmology University of Tübingen Tübingen Germany

Institute of Computational Biology Helmholtz Zentrum München Neuherberg Germany

Institute of Diabetes and Regeneration Research Helmholtz Zentrum München Neuherberg Germany

Paul Langerhans Institute Dresden of the Helmholtz Zentrum Munich at the University Clinic Carl Gustav Carus TU Dresden Dresden Germany

SOTIO a s Jankovcova 1518 2 Prague Czech Republic

Technical University of Munich Department of Mathematics Garching b Munich Germany

Technical University of Munich School of Life Sciences Weihenstephan Freising Germany

Technische Universität München School of Medicine München Germany

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Synaptotagmin-13 orchestrates pancreatic endocrine cell egression and islet morphogenesis