NEFH-tTA transgenic mice have the human neurofilament heavy polypeptide (NEFH) promoter directing expression of tetracycline-controlled transactivator protein (tTA) to neurons with large-caliber axons of the brain and spinal cord. NEFH-tTA transgenic line 8 has its highest tTA expression in developmental late stage of the cortex, cerebellum and hippocampus, with expression also observed in olfactory bulb and in the rest of the brain. When mated to a second strain carrying a gene of interest under the regulatory control of a tetracycline-responsive promoter element (TRE; tetO), expression of the target gene can be blocked by administration of the tetracycline analog, doxycycline (dox).

For example, NEFH-tTA mice are useful in studying brain disorders such as amyotrophic lateral sclerosis (ALS) / frontotemporal lobar degeneration (FTLD) when used in conjunction with tetO-hTDP-43 transgenic mice. Specifically, the regulatable NLS (rNLS8) double transgenic line is created by breeding NEFH-tTA line 8 with TRE-promoter-driven cytoplasmic-insoluble human TDP-43ΔNLS transgenic mice (tetO-hTDP-43-ΔNLS line 4 ; Stock No. 014650). On a mixed C57BL/6J x C3HeJ F1 genetic background, rNLS8 mice exhibit widespread, high levels of hTDP-43ΔNLS expression in neurons of both the brain and spinal cord (SC) as early as 1 week off-dox. The brain/SC combination of hTDP-43-ΔNLS expression accounts for the spinal motor neuron loss and muscle denervation; resulting in a rapid, robust and progressive neurodegenerative ALS-like phenotype (including motor deficits, denervation of neuromuscular junctions, motor neuron loss and premature death at ~8-20 weeks). Upon administration of dox, the observed TDP-43 pathology and functional deficits were found to be largely reversible, even after neurodegeneration was underway (~8 weeks of hTDP-43-ΔNLS expression). Breeding NEFH-tTA with TRE-promoter-driven human TDP-43 wildtype transgenic mice (tetO-hTDP-43-WT line 12 ; Stock No. 016841) provides a regulatable control double transgenic line that exhibits broad nuclear hTDP-43-WT expression in the brain and spinal cord, without the formation of cytoplasmic TDP-43 pathology.
In addition, breeding NEFH-tTA mice to tetO-hα-syn-A53T line 33 (Stock No. 016976) allows studying Parkinson's disease.

Importantly, the donating investigator reports that this human NEFH promoter drives slightly higher levels of tTA expression in the cortex compared to their experiences with the mouse Camk2a promoter used in Camk2a-tTA mice (greater than ~10-fold higher than endogenous NEFH versus ~8-fold higher than endogenous CAMK2A). In addition, the human NEFH promoter directs tTA expression in spinal cord (whereas the mouse Camk2a promoter did not).

Hemizygous NEFH-tTA mice are viable and fertile, have normal lifespan out to latest date tested (18 months) and have no observed abnormalities. Homozygous mice are viable. The donating investigator reports that breeding homozyotes to wildtype animals results in hemizygous offspring, but breeding homozygous mice together did not generate any offspring.