Immunotoxin-mediated conditional disruption of specific neurons in transgenic mice.
We have developed a transgenic approach, termed immunotoxin-mediated cell targeting (IMCT), to ablate conditionally selective neurons in the brain with the cytotoxic activity of immunotoxins. Transgenic mice were created that express the human interleukin 2 receptor alpha subunit (IL-2R alpha) under the control of the dopamine beta-hydroxylase (DBH) gene promoter. The animals were treated intracerebroventricularly with a recombinant immunotoxin, anti-Tac(Fv)-PE40, which selectively kills animal cells bearing human IL-2R alpha. The immunotoxin caused a characteristic behavioral abnormality only in the transgenic mice. This was accompanied by a dramatic loss of DBH-containing neurons and a significant decrease in DBH activity and norepinephrine levels in various regions of the brain. IMCT should provide a general technique to create animal models of human neurodegenerative disorders by targeting neurons or other cell types.
Kobayashi
K
K
Institute for Comprehensive Medical Science, School of Medicine, Fujita Health University, Toyoake, Japan.
Morita
S
S
Sawada
H
H
Mizuguchi
T
T
Yamada
K
K
Nagatsu
I
I
Fujita
K
K
Kreitman
R J
RJ
Pastan
I
I
Nagatsu
T
T
D036002:ADP Ribose Transferases; D000818:Animals; D001427:Bacterial Toxins; D001483:Base Sequence; D017931:DNA Primers; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D005098:Exotoxins; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D011401:Promoter Regions, Genetic; D015375:Receptors, Interleukin-2 / Q000235:genetics; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D017931:DNA Primers; D004299:Dopamine beta-Hydroxylase; D005098:Exotoxins; D000922:Immunotoxins; D015375:Receptors, Interleukin-2; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A