Alzheimer’s disease and other dementias present with tau pathology. Several mouse lines with knockout of the tau-encoding Mapt gene have been reported, yet findings often differed between lines and sites. Here, we report a new tau knockout strain (tauΔex1), generated by CRISPR/Cas9-mediated genome editing of intron -1/exon 1 of Mapt in C57Bl/6J mice. TauΔex1 mice had no overt phenotype, but, in line with previous models, they showed a significantly reduced susceptibility to excitotoxic seizures, with normal memory formation in young mice. This new in vivo resource will be made freely available to the research community.
BallatoreC, LeeVM, TrojanowskiJQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci8, 663–672.
2.
McMillanP, KorvatskaE, PoorkajP, EvstafjevaZ, RobinsonL, GreenupL, LeverenzJ, SchellenbergGD, D’SouzaI (2008) Tau isoform regulation is region- and cell-specific in mouse brain. J Comp Neurol511, 788–803.
3.
LiuC, GotzJ (2013) Profiling murine tau with 0N, 1N and 2N isoform-specific antibodies in brain and peripheral organs reveals distinct subcellular localization, with the 1N isoform being enriched in the nucleus. PLoS One8, e84849.
4.
ShahaniN, BrandtR (2002) Functions and malfunctions of the tau proteins. Cell Mol Life Sci59, 1668–1680.
5.
BiM, GladbachA, van EerselJ, IttnerA, PrzybylaM, van HummelA, ChuaSW, van der HovenJ, LeeWS, MullerJ, ParmarJ, JonquieresGV, StefenH, GuccioneE, FathT, HousleyGD, KlugmannM, KeYD, IttnerLM (2017) Tau exacerbates excitotoxic brain damage in an animal model of stroke. Nat Commun8, 473.
6.
IttnerA, ChuaSW, BertzJ, VolkerlingA, van der HovenJ, GladbachA, PrzybylaM, BiM, van HummelA, StevensCH, IppatiS, SuhLS, MacmillanA, SutherlandG, KrilJJ, SilvaAP, MackayJ, PoljakA, DelerueF, KeYD, IttnerLM (2016) Site-specific phosphorylation of tau inhibits amyloid-beta toxicity in Alzheimer’s mice. Science354, 904–908.
7.
IttnerLM, KeYD, DelerueF, BiM, GladbachA, van EerselJ, WolfingH, ChiengBC, ChristieMJ, NapierIA, EckertA, StaufenbielM, HardemanE, GotzJ (2010) Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell142, 387–397.
8.
GoedertM, SpillantiniMG, CairnsNJ, CrowtherRA (1992) Tau proteins of Alzheimer paired helical filaments: Abnormal phosphorylation of all six brain isoforms. Neuron8, 159–168.
9.
BueeL, BussiereT, Buee-ScherrerV, DelacourteA, HofPR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev33, 95–130.
10.
van SwietenJC, StevensM, RossoSM, RizzuP, JoosseM, de KoningI, KamphorstW, RavidR, SpillantiniMG, Niermeijer, HeutinkP (1999) Phenotypic variation in hereditary frontotemporal dementia with tau mutations. Ann Neurol46, 617–626.
11.
LewisJ, McGowanE, RockwoodJ, MelroseH, NacharajuP, Van SlegtenhorstM, Gwinn-HardyK, Paul MurphyM, BakerM, YuX, DuffK, HardyJ, CorralA, LinWL, YenSH, DicksonDW, DaviesP, HuttonM (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet25, 402–405.
12.
IttnerLM, FathT, KeYD, BiM, van EerselJ, LiKM, GunningP, GotzJ (2008) Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia. Proc Natl Acad Sci U S A105, 15597–16002.
13.
KeYD, SuchowerskaAK, van der HovenJ, De SilvaDM, WuCW, van EerselJ, IttnerA, IttnerLM (2012) Lessons from tau-deficient mice. Int J Alzheimers Dis2012, 873270.
14.
HaradaA, OguchiK, OkabeS, KunoJ, TeradaS, OhshimaT, Sato-YoshitakeR, TakeiY, NodaT, HirokawaN (1994) Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature369, 488–491.
15.
DawsonHN, FerreiraA, EysterMV, GhoshalN, BinderLI, VitekMP (2001) Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J Cell Sci114, 1179–1187.
16.
TakeiY, TengJ, HaradaA, HirokawaN (2000) Defects in axonal elongation and neuronal migration in mice with disrupted tau and map1b genes. J Cell Biol150, 989–1000.
17.
IkegamiS, HaradaA, HirokawaN (2000) Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice. Neurosci Lett279, 129–132.
18.
LeiP, AytonS, FinkelsteinDI, SpoerriL, CiccotostoGD, WrightDK, WongBX, AdlardPA, ChernyRA, LamLQ, RobertsBR, VolitakisI, EganGF, McLeanCA, CappaiR, DuceJA, BushAI (2012) Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med18, 291–295.
19.
MaQL, ZuoX, YangF, UbedaOJ, GantDJ, AlaverdyanM, KioseaNC, NazariS, ChenPP, NothiasF, ChanP, TengE, FrautschySA, ColeGM (2014) Loss of MAP function leads to hippocampal synapse loss and deficits in the Morris Water Maze with aging. J Neurosci34, 7124–7136.
RobersonED, Scearce-LevieK, PalopJJ, YanF, ChengIH, WuT, GersteinH, YuGQ, MuckeL (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science316, 750–754.
22.
MorrisM, HamtoP, AdameA, DevidzeN, MasliahE, MuckeL (2013) Age-appropriate cognition and subtle dopamine-independent motor deficits in aged tau knockout mice. Neurobiol Aging34, 1523–1529.
23.
van HummelA, BiM, IppatiS, van der HovenJ, VolkerlingA, LeeWS, TanDC, BongersA, IttnerA, KeYD, IttnerLM (2016) No overt deficits in aged tau-deficient C57Bl/6.Mapttm1(EGFP)Kit GFP knockin mice. PLoS One11, e0163236.
24.
RapoportM, DawsonHN, BinderLI, VitekMP, FerreiraA (2002) Tau is essential to beta -amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A99, 6364–6369.
25.
DawsonHN, CantillanaV, JansenM, WangH, VitekMP, WilcockDM, LynchJR, LaskowitzDT (2010) Loss of tau elicits axonal degeneration in a mouse model of Alzheimer’s disease. Neuroscience169, 516–531.
26.
PanY, ZhangL, LiuQ, LiY, GuoH, PengY, PengH, TangB, HuZ, ZhaoJ, XiaK, LiJD (2016) Insertion of a knockout-first cassette in Ampd1 gene leads to neonatal death by disruption of neighboring genes expression. Sci Rep6, 35970.
27.
PhamCT, MacIvorDM, HugBA, HeuselJW, LeyTJ (1996) Long-range disruption of gene expression by a selectable marker cassette. Proc Natl Acad Sci U S A93, 13090–13095.
28.
ScacheriPC, CrabtreeJS, NovotnyEA, Garrett-BealL, ChenA, EdgemonKA, MarxSJ, SpiegelAM, ChandrasekharappaSC, CollinsFS (2001) Bidirectional transcriptional activity of PGK-neomycin and unexpected embryonic lethality in heterozygote chimeric knockout mice. Genesis30, 259–263.
29.
DelerueF, IttnerLM (2017) Generation of genetically modified mice through the microinjection of oocytes. J Vis Exp, doi: 10.3791/55765
30.
DelerueF, IttnerLM (2015) Genome editing in mice using CRISPR/Cas9: Achievements and prospects. Clon Transgen4, 2.
31.
TuckerKL, MeyerM, BardeYA (2001) Neurotrophins are required for nerve growth during development. Nat Neurosci4, 29–37.
32.
IttnerLM, KollerD, MuffR, FischerJA, BornW (2005) The N-terminal extracellular domain 23-60 of the calcitonin receptor-like receptor in chimeras with the parathyroid hormone receptor mediates association with receptor activity-modifying protein 1. Biochemistry44, 5749–5754.
33.
GladbachA, van EerselJ, BiM, KeYD, IttnerLM (2014) ERK inhibition with PD184161 mitigates brain damage in a mouse model of stroke. J Neural Transm121, 543–547.
34.
KeYD, van HummelA, StevensCH, GladbachA, IppatiS, BiM, LeeWS, KrugerS, van der HovenJ, VolkerlingA, BongersA, HallidayG, HaassNK, KiernanM, DelerueF, IttnerLM (2015) Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS. Acta Neuropathol130, 661–678.
35.
GartheA, KempermannG (2013) An old test for new neurons: Refining the Morris water maze to study the functional relevance of adult hippocampal neurogenesis. Front Neurosci7, 63.
