Retinoic acid signaling within pancreatic endocrine progenitors regulates mouse and human β cell specification

Development. 2020 Jun 22;147(12):dev189977. doi: 10.1242/dev.189977.

Abstract

Retinoic acid (RA) signaling is essential for multiple developmental processes, including appropriate pancreas formation from the foregut endoderm. RA is also required to generate pancreatic progenitors from human pluripotent stem cells. However, the role of RA signaling during endocrine specification has not been fully explored. In this study, we demonstrate that the disruption of RA signaling within the NEUROG3-expressing endocrine progenitor population impairs mouse β cell differentiation and induces ectopic expression of crucial δ cell genes, including somatostatin. In addition, the inhibition of the RA pathway in hESC-derived pancreatic progenitors downstream of NEUROG3 induction impairs insulin expression. We further determine that RA-mediated regulation of endocrine cell differentiation occurs through Wnt pathway components. Together, these data demonstrate the importance of RA signaling in endocrine specification and identify conserved mechanisms by which RA signaling directs pancreatic endocrine cell fate.

Keywords: Diabetes; Pancreas development; Retinoic acid signaling; Wnt signaling; β cell differentiation; δ cell specification.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / deficiency
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Differentiation
  • Embryo, Mammalian / metabolism
  • Homeodomain Proteins / genetics
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Pancreas / cytology
  • Pancreas / metabolism*
  • Receptors, Retinoic Acid / deficiency
  • Receptors, Retinoic Acid / genetics
  • Signal Transduction*
  • Somatostatin / genetics
  • Somatostatin / metabolism
  • Somatostatin-Secreting Cells / cytology
  • Somatostatin-Secreting Cells / metabolism
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Tretinoin / metabolism*
  • Wnt Proteins / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • Insulin
  • Nerve Tissue Proteins
  • Neurog3 protein, mouse
  • Receptors, Retinoic Acid
  • Trans-Activators
  • Wnt Proteins
  • pancreatic and duodenal homeobox 1 protein
  • Somatostatin
  • Tretinoin