Robo signalling controls pancreatic progenitor identity by regulating Tead transcription factors

Nat Commun. 2018 Nov 30;9(1):5082. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dyneins / genetics
  • Dyneins / metabolism
  • Immunohistochemistry
  • In Situ Hybridization
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Pancreas / cytology*
  • Pancreas / metabolism*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Stem Cells / cytology*
  • Stem Cells / metabolism*
  • TEA Domain Transcription Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • DNA-Binding Proteins
  • Membrane Proteins
  • Receptors, Immunologic
  • Robo2 protein, mouse
  • Slit3 protein, mouse
  • TEA Domain Transcription Factors
  • Tead2 protein, mouse
  • Transcription Factors
  • Dyneins
  • roadblock 1 protein, mouse