The Arc^CreER knock-in/knockout allele was designed to both abolish activity regulated cytoskeletal-associated protein (Arc) gene function and express CreER^T2 (CreERT2) fusion protein from the endogenous Arc promoter/enhancer elements. The donating investigator did not determine if endogenous gene mRNA/protein is expressed from the mutant allele. CreERT2 fusion protein activity is inducible; observed following tamoxifen administration. When Arc^CreER mice are bred with mice containing loxP-flanked sequences, tamoxifen-inducible Cre-mediated recombination will result in deletion of floxed sequences in the Arc-expressing cells of the offspring.

Specifically, the donating investigator reports that following tamoxifen induction, Cre recombinase activity is observed in active populations of neurons in the brain in a pattern consistent with endogenous Arc expression. Some CreERT2 activity is observed in the brain prior to tamoxifen exposure (sub-populations of neurons in the brain, including in layer 6 neocortical cells and dentate gyrus granule cells, as well as sparser populations of other cell types). Additionally, a small number of offspring show Cre recombinase activity in the germline (both with or without tamoxifen). The donating investigator did not examine CreERT2 activity in tissues other than brain.

While other Arc null mutations are published with behavioral/neurological defects and embryonic lethality, the donating investigator reports that Arc^CreER homozygotes are viable and fertile with no behavioral/neurological defects grossly observed. More detailed behavioral/physiological characterization of homozygous mice has not been evaluated to date (April 2013).

The Cre-ERT2 fusion protein consists of Cre recombinase fused to a triple mutant form of the human estrogen receptor which does not bind its natural ligand (17β-estradiol) at physiological concentrations but will bind the synthetic estrogen receptor ligands 4-hydroxytamoxifen (OHT or tamoxifen) and, with lesser sensitivity, ICI 182780. Restricted to the cytoplasm, Cre-ERT2 can only gain access to the nuclear compartment after exposure to tamoxifen. To counteract the mixed estrogen agonist effects of tamoxifen injections, which can result in late fetal abortions in pregnant mice, progesterone may be coadministered.