Posted 30 September 2004

General Information

cDNA construction: A 1.35-kb porcine TGF-b1 cDNA was kindly provided by Dr. A. H. Greenberg (Manitoba Institute of Cell Biology, Winnipeg, Canada).

The cDNA was inserted into the first exon of a modified mouse glial fibrillary acidic protein (GFAP) gene. It is mutated to encode serines instead of cysteines at amino acid positions 223 and 225 to ensure that TGF-β1 is secreted as a bioactive peptide.

Tg mice line T64 is a low TGF-β1 expresser, but has more protein by immunohistochemistry than T115 (aka T65), especially in the hippocampus.

Mutation: TGF-β1

Promoter:  mouse GFAP

Origin: BALB/c × SJL background and heterozygous for TGF-β1

Background: C57BL/6J; generations 10.

Breeding: Mice breed but have small litters with occasional mice with hydrocephalus (5-10% of transgenics - probably due to transgene upregulation in some mice)

Phenotype

Neuropathological analysis

T64 heterozygous mice express half the levels of cerebral TGF-β1 mRNA than T115 het mice. In both lines, TGF-β1 is produced by brain astrocytes from birth and is most prominent in perivascular locations.

In 9- and 18-month-old TGF-β1 T64 mice, degenerative changes in microvascular cells of the brain were observed. Endothelial cells were thinner and displayed abnormal, microvilli-like protrusions as well as occasional condensation of chromatin, and pericytes occupied smaller areas in capillary profiles than in nontg controls. Thus chronic overproduction of TGF-β1 triggers an accumulation of basement membrane proteins and results in AD-like cerebrovascular amyloidosis and microvascular degeneration.

Transgene copy number: approximately 1

mRNA levels: -/+ 100 (het) +/+ 700

Hydrocephalus: 5-20 % penetrance in heterozygous mice depending on strain; 100% penetrance in homozygous mice

Other pathology: Cerebrovascular astrocytosis and amyloid deposition is age- and dose-related. In addition, genetic background of strain modulates pathology.

Behavioral

Homozygous mice display neurological complications such as tremors, seizures, incoordination, runting and severe hydrocephalus.

Availability

Licensing/academic distribution contact information:

Contact: Tony Wyss-Coray
VA Palo Alto Health Care System, Mailcode 154W, Bldg 100 D3-141
Stanford University, 300 Pasteur Drive, Stanford, CA 94305
Tel: 650-852-3220, Fax: 650-849-0434
Email: twc@stanford.edu

Patents: None

References

Primary:

Wyss-Coray T, Feng L, Masliah E, Ruppe MD, Lee HS, Toggas SM, Rockenstein EM, Mucke L: Increased central nervous system production of extracellular matrix components and development of hydrocephalus in transgenic mice overexpressing transforming growth factor-ß1. Am J Pathol 147:53-67, 1995. Abstract

Associated:

Wyss-Coray, C. Lin, D.A. Sanan, L. Mucke and E. Masliah. Chronic overproduction of transforming growth factor-ß1 by astrocytes promotes Alzheimer's disease-like microvascular degeneration in transgenic mice. Am. J. Pathol. 156:139-150, 2000. Abstract

Wyss-Coray, T., Borrow, P., Brooker, M.J., and Mucke, L. Astroglial overproduction of TGF-b1 enhances inflammatory central nervous system disease in transgenic mice. J. Neuroimmunol. 77:45-50, 1997. Abstract

Wyss-Coray, T., Masliah, E., Mallory, M., McConlogue, L., Johnson-Wood, K., Lin, C., and Mucke, L. (1997) Amyloidogenic role of cytokine TGF-b1 in transgenic mice and Alzheimer's disease. Nature 389:603-606. Abstract