Posted 28 January 2005

General Information

Transgene: Developed a floxed PS1 mouse (PS1 exons 2 and 3 are flanked by two loxP sites) (Yu et al., 2000 and 2001), crossed with Nestin-Cre transgenic mice (Tronche et al., 1999) to obtain mice heterozygous for the fPS1 allele and hemizygous for the Nestin-Cre allele, then crossed with fPS1/fPS1 mice to obtain PS1 cKO (fPS1/fPS1;Nestin-Cre or fPS1/fPS1^Δ;Nestin-Cre) mice. Because PS1 cKO mice die at 2-3 months of age, they were not ideally suited to be used as breeding mice. We therefore crossed fPS1/fPS1^Δ;Nestin-Cre with fPS1/+ to obtain +/fPS1^Δ;Nestin-Cre mice, which were then crossed with fPS1/fPS1 female mice to obtain fPS1/fPS1^Δ;Nestin-Cre (PS1 cKO) and fPS1/+ (control) mice at a ratio of 1:1, due to the linkage between the fPS1^Δ and Nestin-Cre alleles.

Mutation: CNS-restricted PS1 deletion

Promoter: Nestin promoter

Mouse Strain: B6/129: We have both floxed PS1 and Nestin-Cre mice that have been backcrossed to B6 for over 12 generations.

Phenotype

Neuropathological Analysis:

Conditional knockout (cKO) mouse in which PS1 inactivation is restricted to neural progenitor cells (NPCs) and NPC-derived neurons and glia. Neural progenitor and neuronal populations are greatly reduced, due to premature differentiation of neural progenitor cells. Generation and survival of Cajal-Retzius (CR) neurons are unaffected in PS1 cKO mice compared to PS1null mice that show premature loss. 45% of late-born neurons fail to migrate to their appropriate positions in the superficial cortical layer while early born neurons are properly positioned in the deeper cortical layers.

Behavioral:

These mice are smaller in size and show many gross behavioral deficits. They can survive up to 3-4 months of age.

Availability

J. Shen
Center for Neurologic Diseases
Brigham and Woman's Hospital
Boston, MA 02115 USA and Program in Neuroscience
Harvard Medical School
Boston, MA 02115 USA
Phone: (617) 525-5561
Fax: (617) 525-5522
Email: jshen@rics.bwh.harvard.edu

Patents: None

Primary Reference

Wines-Samuelson M, Handler M, Shen J. Role of presenilin-1 in cortical lamination and survival of Cajal-Retzius neurons. Dev Biol. 277(2):332-46, 2005. Abstract

Associated References

Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban P, Bock R, Klein R, Schutz G. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat. Genet. 23:99-103, 1999. Abstract

Yu H, Kessler J, Shen J. Heterogeneous populations of Es cells in the generation of a floxed presenilin-1 allele. Genesis 26:5-8, 2000. Abstract

Yu H, Saura CA, Choi S-Y, Sun L D, Yang X, Handler M, Kawarabayashi T, Younkin L, Fedeles B, Wilson M A, Younkin S, Kandel E R, Kirkwood A, Shen J. APP processing and synaptic plasticity in presenilin-1 conditional knockout mice. Neuron 31:713-726, 2001. Abstract