A transcriptomic roadmap to alpha- and beta cell differentiation in the embryonic pancreas

Abstract

During pancreatic development, endocrine cells appear from the pancreatic epithelium when Neurog3 positive cells delaminate and differentiate into alpha, beta, gamma and delta cells. The mechanisms involved in this process are still incompletely understood. We characterized the temporal, lineage-specific developmental programs during pancreatic development by sequencing the transcriptome of thousands of individual pancreatic cells from embryonic day E12.5 to E18.5 in mice, and identified all known cell types that are present in the embryonic pancreas, but focused specifically on alpha and beta cell differentiation by enrichment of a MIP-GFP reporter. We characterized transcriptomic heterogeneity in the tip domain based on proliferation, and characterized two endocrine precursor clusters marked by expression of Neurog3 and Fev. Pseudotime analysis revealed specific branches for developing alpha- and beta cells, which allowed identification of specific gene regulation patterns. These include some known and many previously unreported genes that appear to define pancreatic cell fate transitions. This resource allows dynamic profiling of embryonic pancreas development at single cell resolution and reveals novel gene signatures during pancreatic differentiation into alpha and beta cells.