Posted 3 February 2011
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.
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.
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.
Motor impairment observed in tTA/TDP-ΔNLS mice.
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.
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.