Experimental control of pancreatic development and maintenance

Andrew M. Holland, Michael A. Hale, Hideaki Kagami, Robert E Hammer, Raymond J MacDonald

Research output: Contribution to journalArticle

164 Citations (Scopus)

Abstract

To investigate the role of the HOX-like homeoprotein PDX1 in the formation and maintenance of the pancreas, we have genetically engineered mice so that the only source of PDX1 is a transgene that can be controlled by the application of tetracycline or its analogue doxycycline. In these mice the coding region for the tetracycline-regulated transactivator (tTAoff) has replaced the coding region of the endogenous Pdx1 gene to ensure correct temporal and spatial expression of the regulatable transactivator. In the absence of doxycycline, tTAoff activates the transcription of a bicistronic transgene encoding PDX1 and an enhanced green fluorescent protein reporter, which acts as a visual marker of transgene expression in living cells. Expression of the transgene-encoded PDX1 rescues the Pdx1-null phenotype; the pancreata of these mice develop and function normally. The rescue is conditional; doxycycline-mediated repression of the transgenic Pdx1 throughout gestation recapitulates the Pdx1 null phenotype. Moreover, application of doxycycline at mid-pancreogenesis blocks further development. Adult animals of the rescue genotype that were treated with doxycycline for 3 weeks shut off Pdx1 expression, decreased insulin production, and lost the ability to maintain glucose homeostasis. These results demonstrate the feasibility of controlling the formation of an organ during embryogenesis in utero and the maintenance of the mature organ through the experimental manipulation of a key developmental regulator.

Original languageEnglish (US)
Pages (from-to)12236-12241
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number19
DOIs
StatePublished - Sep 17 2002

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Doxycycline
Transgenes
Maintenance
Trans-Activators
Tetracycline
Pancreas
Phenotype
Homeodomain Proteins
Embryonic Development
Homeostasis
Genotype
Insulin
Glucose
Pregnancy
Genes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Experimental control of pancreatic development and maintenance. / Holland, Andrew M.; Hale, Michael A.; Kagami, Hideaki; Hammer, Robert E; MacDonald, Raymond J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 19, 17.09.2002, p. 12236-12241.

Research output: Contribution to journalArticle

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