Posted 13 August 2010

General Information

Transgene: The pgrn locus was flanked with loxP sites to bracket the promoter and the first four exons in a BAC targeting vector. Three positive CY2.4 ES clones with homozygous C57BL/6J/Tyr^C-21 genetic background were injected into C57BL/6 blastocysts. Chimeras were identified and crossed with C57BL/6J to obtain the germline-transmitted heterozygous floxed mice (pgrn^flox/+). Mating between two heterozygous mice generated homozygous floxed mice (pgrn^flox/flox). Breeding of pgrn^flox/+ or pgrn^flox/flox mice with CAG-Cre mice (backcrossed to C57BL/6) resulted in both Cre-positive and Cre-negative mice with ubiquitous deletions of the pgrn gene and the neo/kan cassette. The progranulin knockout mice are cre-negative.

Mutation:

Breeding: Normal. Origin: N >10 to C57BL/6.

Mouse strain: C57BL/6

Phenotype

Neuropathological Analysis:

PGRN deficiency associated with hyper-inflammatory phenotype in activated macrophages and microglia, which accelerated the damage of neurons. 12-month mice showed progressive development of neuropathology (enhanced activation of microglia and astrocytes and cytoplamic accumulation of phos TDP-43). FTD-like neuropathological deficits.

Behavioral Phenotype:

Young-adult mice were healthy and fertile. They displayed increased depression- and disinhibition-like behavior as well as deficits in social recognition. No deficits in locomotion or exploration. 18-month mice showed impaired spatial learning and memory.

Availability

Contact: Aihao Ding
Dept. Microbiology and Immunology
Weill Cornell Medical College
1300 York Ave., New York, NY 10065
Phone: 212-746-4551
Fax: 212-746-8536
E-mail: ahding@med.cornell.edu.

These mice are in the process of being transferred to The Jackson Laboratory repository.

References

Primary:

Yin F, Banerjee R, Thomas B, Zhou P, Qian L, Jia T, Ma X, Ma Y, Iadecola C, Beal MF, Nathan C, Ding A. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med. 2010 Jan 18;207(1):117-28. Abstract

Yin F, Dumont M, Banerjee R, Ma Y, Li H, Lin MT, Beal MF, Nathan C, Thomas B, Ding A. Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia. FASEB J. 2010 Jul 28. Abstract