Nucleo-cytoplasmic shuttling of fused in sarcoma (FUS) occurs by a nuclear localization signal (NLS). The majority of clinical amyotrophic lateral sclerosis (ALS; Lou Gehrig's Disease) and frontotemporal lobar degeneration (FTLD)-associated FUS mutations occur in its C-terminal NLS sequence. Overexpression of wildtype FUS protein can be pathogenic in human patients as well.

CAG-Z-FUS^WT-IRES-EGFP transgenic line 629 (simply called CAG-Z-FUS^WT (629)) has a floxed-lacZ gene preventing transcription of the downstream bicistronic sequences; a wildtype human fused in sarcoma protein (huFUS^WT) and EGFP. Prior to Cre recombinase exposure, lacZ expression is directed to widespread tissues by the CAG promoter, and no expression of huFUS^WT or EGFP is observed. When bred to mice that express Cre recombinase, the resulting offspring will have the floxed-lacZ deleted in the cre-expressing tissues; resulting in expression of huFUS^WT and EGFP fluorescence in cre-expressing tissues (and continued lacZ expression in other tissues).

Mice hemizygous for the CAG-Z-FUS^WT transgene are viable and fertile, born at normal Mendelian ratios, and have no reported phenotypic abnormalities. To date (September 2015), it has not been attempted to make this strain homozygous.

When CAG-Z-FUS^WT (629) are bred to C57BL/6-congenic Meox2^Cre knock-in animals (Stock No. 003755), germline deletion of floxed-lacZ generates the CAG-FUS^WT-IRES-EGFP genotype (simply called CAG-FUS^WT). Mice hemizygous for the CAG-FUS^WT transgene and heterozygous for Meox2^Cre (Tg/+ , +/Cre) have global overexpression of low levels of huFUS^WT, resulting in severe deficits in motor function, denervation of the neuromuscular junctions (NMJs), muscle atrophy, neuroinflammation and early lethality (none survive to adulthood; nearly 100% die by postnatal day 30). The level of huFUS^WT expression was similar to that of endogenous mouse FUS, resulting in ~2-fold expression levels of total FUS (huFUS^WT + mouse FUS) compared to control mice.

In addition, both CAG-FUS^R521G (Stock No. 028021 with germline deletion of floxed-lacZ) and CAG-FUS^WT transgenic mouse models exhibit no overt motor neuron loss, no apparent ubiquitin-positive aggregation and no mislocalization of FUS in neurons and glia. Transcriptomic analysis of spinal cords revealed that the gene expression pattern is altered in CAG-FUS^WT mice, but not significantly altered in CAG-FUS^R521G mice. The CAG-FUS^WT and CAG-FUS^R521G animals display some characteristics of adult ALS. However, the onset of phenotype in the mouse models is earlier, more closely reflecting FUS-linked juvenile ALS.