Transcriptional autoregulation controls pancreatic Ptf1a expression during development and adulthood

Toshihiko Masui, Galvin H. Swift, Michael A. Hale, David M. Meredith, Jane E. Johnson, Raymond J. MacDonald

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

The basic helix-loop-helix (bHLH) transcription factor PTF1a is critical to the development of the embryonic pancreas. It is required early for the formation of the undifferentiated tubular epithelium of the nascent pancreatic rudiment and then becomes restricted to the differentiating acinar cells, where it directs the transcriptional activation of the secretory digestive enzyme genes. Here we report that the complex temporal and spatial expression of Ptf1a is controlled by at least three separable gene-flanking regions. A 14.8-kb control domain immediately downstream of the last Ptf1a exon is highly conserved among mammals and directs expression in the dorsal part of the spinal cord but has very little activity in the embryonic or neonatal pancreas. A 13.4-kb proximal promoter domain initiates limited expression in cells that begin the acinar differentiation program. The activity of the proximal promoter domain is complemented by an adjacent 2.3-kb autoregulatory enhancer that is able to activate a heterologous minimal promoter with high-level penetrance in the pancreases of transgenic mice. During embryonic development, the enhancer initiates expression in the early precursor epithelium and then superinduces expression in acinar cells at the onset of their development. The enhancer contains two evolutionarily conserved binding sites for the active form of PTF1a, a trimeric complex composed of PTF1a, one of the common bHLH E proteins, and either RBPJ or RBPJL. The two sites are essential for acinar cell-specific transcription in transfected cell lines and mice. In mature acinar cells, the enhancer and PTF1a establish an autoregulatory loop that reinforces and maintains Ptf1a expression. Indeed, the trimeric PTF1 complex forms dual autoregulatory loops with the Ptf1a and Rbpjl genes that may maintain the stable phenotype of pancreatic acinar cells.

Original languageEnglish (US)
Pages (from-to)5458-5468
Number of pages11
JournalMolecular and Cellular Biology
Volume28
Issue number17
DOIs
StatePublished - Sep 2008

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Acinar Cells
Homeostasis
Pancreas
Embryonic Development
Epithelium
Genes
Basic Helix-Loop-Helix Transcription Factors
Penetrance
Transgenic Mice
Transcriptional Activation
Mammals
Exons
Spinal Cord
Binding Sites
Phenotype
Cell Line
Enzymes
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Transcriptional autoregulation controls pancreatic Ptf1a expression during development and adulthood. / Masui, Toshihiko; Swift, Galvin H.; Hale, Michael A.; Meredith, David M.; Johnson, Jane E.; MacDonald, Raymond J.

In: Molecular and Cellular Biology, Vol. 28, No. 17, 09.2008, p. 5458-5468.

Research output: Contribution to journalArticle

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