Loss of NPC1 (Niemann Pick type C1) protein function is a known cause of Niemann-Pick type C disease, a fatal lysosomal storage disorder associated with progressive, widespread neurological deterioration. Symptoms include, but are not limited to, dementia, ataxia, dysarthria, dystonia, and epilepsy.
In this transgenic strain, expression of YFP-labeled and FLAG-tagged NPC1 is conditionally directed via a tetracycline-inducible minimal cytomegalovirus (tetO-CMVmin) promoter. When bred with mice expressing reverse tetracycline-controlled transactivator protein (rtTA) or tetracycline-controlled transactivator protein (tTA), NPC1-YFP expression can be regulated with the tetracycline analog doxycycline (dox) in the resulting double mutant offspring. Expression of the transgene is undetectable in heterozygotes in the absence of a tTA/rtTA driver.
Founder lines were test-crossed with Pcp2-tTA (Purkinje cell protein 2 (L7)) driver animals (see Stock No. 005625) to select a transgenic line that best exhibited induction of NPC1-YFP in Purkinje neuron layer of the mouse cerebellum.
When tetO/tTA (or tetO/rtTA) double mutants are further combined with an Npc1 knockout (see Stock No. 021755), cell type-specific rescue of NPC1 loss can be tested. NPC1-YFP produced in cerebellar Purkinje neurons of Npc1 knockout mice prevents neuron degeneration, slows reactive glial activity, and ameliorates disease. These mice show reduced ataxia, increased weight, and prolonged life, but the transgene does not prevent the eventual decline and premature death of knockout mice. Cell types responsible for disease pathogenesis can be traced through the fluorescent signal.
Robust expression of NPC1-YFP in skin and visceral tissue is observed in offspring generated through crosses with B6.Cg-Gt(ROSA)26Sortm1(rtTA*M2)Jae (see Stock No. 006965) and treated with dox.
