Transgenic mice with a mutated collagen promoter display normal response during bleomycin-induced fibrosis and possess neurological abnormalities

John H. Stoddart, Daniel Ladd, Roderick T. Bronson, Michael Harmon, James Jaworski, Carole Pritzker, Niels Lausen, Barbara D. Smith

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

We have previously identified a potential TGF-β activation element (TAE) in the rat collagen α1(I) promoter at -1624 upstream of the transcriptional start site [Ritzenthaler et al., 1991, 1993]. To determine the importance of the TAE in vivo, we produced transgenic mice carrying 3.6 kb of the rat collagen α1 (I) promoter linked to the reporter gene chloramphenicol acetyl transferase with and without site-directed mutations that eliminate DNA-protein binding at the TAE site. Tissue-specific expression of the reporter gene in transgenic mice with the mutated collagen promoter was similar to that of transgenic mice with the normal promoter in two genetic backgrounds as judged by in situ hybridization, reporter assays, and immunochemistry. Endotracheal instillation of bleomycin induces lung fibrosis, mediated in part by TGF-β. Earlier studies indicated that expression of wild-type collagen-reporter gene was upregulated in transgenic mice lungs in response to endotracheal instillation of bleomycin. A similar level of reporter gene upregulation was observed in transgenic mice carrying the mutation in the TAE. Two lines of transgenic mice carrying the mutated promoter construct displayed unexpected neurological abnormalities. In the FVB genetic background, there was a higher than normal incidence of mortality, spontaneous seizures, and an inability to nurture offspring. Histological evidence demonstrated clear abnormalities, including disorderly arrangement of neurons in the hippocampus and significant laminar cortical necrosis in the cerebrum in animals after seizures. In the C57BI/6 background, them was a high incidence of severe communicating hydrocephalus, early runting, and increased mortality similar to that in transgenic animals with astroglial overexpression of TGF-β. These animals provide an interesting model system to investigate molecular mechanisms responsible for seizures and hydrocephalus. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)135-148
Number of pages14
JournalJournal of Cellular Biochemistry
Volume77
Issue number1
DOIs
StatePublished - 2000
Externally publishedYes

Keywords

  • Collagen
  • Lung fibrosis
  • Neuropathology
  • TGF-β
  • Transgenic mice

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