Robo signalling controls pancreatic progenitor identity by regulating Tead transcription factors

Sophie Escot,Heike Naumann,David Willnow,Silvia Di Francescantonio,Francesca M. Spagnoli

doi:10.1038/s41467-018-07474-6

Abstract

A complex interplay of intrinsic factors and extrinsic signalling pathways controls both cell lineage commitment and maintenance of cell identity. Loss of defined cellular states is the cause of many different cancers, including pancreatic cancer. Recent findings suggest a clinical role for the conserved SLIT/ROBO signalling pathway in pancreatic cancer. However, whilst this pathway has been extensively studied in many processes, a role for Slit and Robo genes in pancreas cell identity and plasticity has not been established yet. Here, we identify Slit/Robo signalling as a key regulator of pancreatic progenitor identity. We find that Robo1 and Robo2 are required for preserving pancreatic cell identity shortly after fate induction and, subsequently, for expansion of the pancreatic progenitor pool in the mouse. Furthermore, we show that Robo receptors control the expression of Tead transcription factors as well as its downstream transcriptional activity. Our work identifies an interplay between Slit/Robo pathway and Tead intrinsic regulators, functioning as gatekeeper of pancreatic cell identity.

Highlights

A complex interplay of intrinsic factors and extrinsic signalling pathways controls both cell lineage commitment and maintenance of cell identity
By RNA-sequencing (RNA-Seq) analysis on cells isolated from mouse foregut endoderm and embryonic pancreas between embryonic stage (E) 8.5 to E10.519, we discovered a spatially distinct expression of Robo[1] and Robo[2] in early pancreatic progenitors
In line with the RNA-Seq data[19], at E10.5 we found that Robo[1] and Robo[2] are abundantly expressed in ventral pancreatic progenitors and very low or absent in dorsal pancreas and liver (Fig. 1a, b)

Summary

Introduction

A complex interplay of intrinsic factors and extrinsic signalling pathways controls both cell lineage commitment and maintenance of cell identity. Recent findings suggest a clinical role for the conserved SLIT/ROBO signalling pathway in pancreatic cancer. Our work identifies an interplay between Slit/Robo pathway and Tead intrinsic regulators, functioning as gatekeeper of pancreatic cell identity. Recent observations suggested a role for local Slit secretion in the survival and function of pancreatic beta-cells in the adult pancreas[14], while Robo receptors are required in the beta-cells for endocrine cell sorting and mature islet architecture[18]. It is not known whether Slit/Robo signalling pathway functions in the establishment and maintenance of pancreatic cell identity and differentiation. Our findings reveal a role for Slit/Robo in pancreatic progenitors, expanding the vast array of biological functions already attributed to this conserved pathway

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Conclusion