Early pancreatic development requires the vertebrate Suppressor of Hairless (RBPJ) in the PTF1 bHLH complex

Toshihiko Masui, Qiaoming Long, Thomas M. Beres, Mark A. Magnuson, Raymond J. MacDonald

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

PTF1a is an unusual basic helix-loop-helix (bHLH) transcription factor that is required for the development of the pancreas. We show that early in pancreatic development, active PTF1a requires interaction with RBPJ, the vertebrate Suppressor of Hairless, within a stable trimeric DNA-binding complex (PTF1). Later, as acinar cell development begins, RBPJ is swapped for RBPJL, the constitutively active, pancreas-restricted paralog of RBPJ. Moreover, the Rbpjl gene is a direct target of the PTF1 complex: At the onset of acinar cell development when the Rbpjl gene is first induced, a PTF1 complex containing RBPJ is bound to the Rbpjl promoter. As development proceeds, RBPJL gradually replaces RBPJ in the PTF1 complex bound to Rbpjl and appears on the binding sites for the complex in the promoters of other acinar-specific genes, including those for the secretory digestive enzymes. A single amino acid change in PTF1a that eliminates its ability to bind RBPJ (but does not affect its binding to RBPJL) causes pancreatic development to truncate at an immature stage, without the formation of acini or islets. These results indicate that the interaction between PTF1a and RBPJ is required for the early stage of pancreatic growth, morphogenesis, and lineage fate decisions. The defects in pancreatic development phenocopy those of Ptf1a-null embryos; thus, the first critical function of PTF1a is in the context of the PTF1 complex containing RBPJ. Action within an organ-specific transcription factor is a previously unknown function for RBPJ and is independent of its role in Notch signaling.

Original languageEnglish (US)
Pages (from-to)2629-2643
Number of pages15
JournalGenes and Development
Volume21
Issue number20
DOIs
StatePublished - Oct 15 2007

Fingerprint

Vertebrates
Acinar Cells
Pancreas
Genes
Basic Helix-Loop-Helix Transcription Factors
Morphogenesis
Transcription Factors
Embryonic Structures
Binding Sites
Amino Acids
DNA
Enzymes
Growth

Keywords

  • Acinar cell
  • Basic helix-loop-helix
  • Notch signaling
  • Pancreas
  • Ptf1a
  • Rbpj

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Early pancreatic development requires the vertebrate Suppressor of Hairless (RBPJ) in the PTF1 bHLH complex. / Masui, Toshihiko; Long, Qiaoming; Beres, Thomas M.; Magnuson, Mark A.; MacDonald, Raymond J.

In: Genes and Development, Vol. 21, No. 20, 15.10.2007, p. 2629-2643.

Research output: Contribution to journalArticle

Masui, Toshihiko ; Long, Qiaoming ; Beres, Thomas M. ; Magnuson, Mark A. ; MacDonald, Raymond J. / Early pancreatic development requires the vertebrate Suppressor of Hairless (RBPJ) in the PTF1 bHLH complex. In: Genes and Development. 2007 ; Vol. 21, No. 20. pp. 2629-2643.
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AU - Long, Qiaoming

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AU - Magnuson, Mark A.

AU - MacDonald, Raymond J.

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AB - PTF1a is an unusual basic helix-loop-helix (bHLH) transcription factor that is required for the development of the pancreas. We show that early in pancreatic development, active PTF1a requires interaction with RBPJ, the vertebrate Suppressor of Hairless, within a stable trimeric DNA-binding complex (PTF1). Later, as acinar cell development begins, RBPJ is swapped for RBPJL, the constitutively active, pancreas-restricted paralog of RBPJ. Moreover, the Rbpjl gene is a direct target of the PTF1 complex: At the onset of acinar cell development when the Rbpjl gene is first induced, a PTF1 complex containing RBPJ is bound to the Rbpjl promoter. As development proceeds, RBPJL gradually replaces RBPJ in the PTF1 complex bound to Rbpjl and appears on the binding sites for the complex in the promoters of other acinar-specific genes, including those for the secretory digestive enzymes. A single amino acid change in PTF1a that eliminates its ability to bind RBPJ (but does not affect its binding to RBPJL) causes pancreatic development to truncate at an immature stage, without the formation of acini or islets. These results indicate that the interaction between PTF1a and RBPJ is required for the early stage of pancreatic growth, morphogenesis, and lineage fate decisions. The defects in pancreatic development phenocopy those of Ptf1a-null embryos; thus, the first critical function of PTF1a is in the context of the PTF1 complex containing RBPJ. Action within an organ-specific transcription factor is a previously unknown function for RBPJ and is independent of its role in Notch signaling.

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