Posted 3 February 2011

General Information

hTDP-43 Tg lines were generated by injection of linearized moPrP-tetP vector containing hTDP-43-WT and hTDP-43-ΔNLS cDNA into pronucleus of fertilized eggs from C57BL/6J × C3HeJ F1 matings. Monogenic tetO-TDP-WT and tetO-TDP-ΔNLS mice were bred to Camk2a-tTA mice generating nTg, tTA monogenic, single tetO-TDP-43 Tg mice, and bigenic mice expressing hTDP-43-WT or hTDP-43-ΔNLS.

Mutation: N/A

Promoter: The tetracycline promoter from pTetSplice with two exons, one intron, and the original 39 UTR of the moPrP.XhoI vector (Jankowsky et al., 2005).

Mouse strain: C57BL/6J-C3HeJ. Bigenic mice (Camk2a-tTA x tetO-hTDP-43) were maintained on Doxycycline to inhibit transgene expression until 28 days of age when they were switched to standard chow to induce hTDP-43 expression.

Phenotype

Neuropathological analysis:

hTDP-43-ΔNLS mice express hTDP-43 with a defective nuclear localization signal in forebrain and changes in gene expression in cortical neurons. Downregulation of endogenous nuclear mTDP-43 was seen in both hTDP-43-WT and hTDP-43-ΔNLS mice, it is plausible that perturbation of nuclear TDP-43 protein levels leads to dysregulation of endogenous mTDP-43 expression, which culminates in neuron death.

Behavioral Phenotype:

Motor impairment observed in tTA/TDP-ΔNLS mice.

Availability

Contact: Virginia M-Y. Lee
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Maloney 3, HUP, 3600 Spruce Street, Philadelphia, Pennsylvania 19104-4283, Phone: 215.662.6427, Fax: 215.349.5909.

References

Primary:

Igaz LM, Kwong LK, Lee EB, Chen-Plotkin A, Swanson E, Unger T, Malunda J, Xu Y, Winton MJ, Trojanowski JQ, Lee VM. Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J Clin Invest. 2011 Jan 4. Abstract