TY - JOUR
T1 - Autonomic neuropathy in transgenic mice caused by immunotoxin targeting of the peripheral nervous system
AU - Sawada, Hirohide
AU - Nishii, Kazuhiro
AU - Suzuki, Tatsuyo
AU - Hasegawa, Kayo
AU - Hata, Tadayoshi
AU - Nagatsu, Ikuko
AU - Kreitman, Robert J.
AU - Pastan, Ira
AU - Nagatsu, Toshiharu
AU - Kobayashi, Kazuto
PY - 1998/1/15
Y1 - 1998/1/15
N2 - Autonomic neuropathy in several neurodegenerative disorders results from disturbance in physiological functions of different cell types in the central and peripheral nervous systems. For a clearer understanding of the etiology and pathogenesis of the autonomic disorders it is necessary to create animal models in which degeneration of the causative neuronal types can be induced. Immunotoxin-mediated cell targeting (IMCT) is a novel transgenic mouse technology for eliminating selective cell types with the cytotoxic activity of a recombinant immunotoxin anti-Tac(Fv)-PE40. In this study we conditionally disrupted peripheral catecholaminergic cells with IMCT to generate a mouse model developing autonomic failure based on primary defects of the sympathetic nervous system. Transgenic mice expressing human interleukin-2 receptor α subunit under the control of the dopamine β- hydroxylase gene promoter were intravenously treated with a proper dose of anti-Tac(Fv)-PE40. The immunotoxin induced a selective loss of the target cells in peripheral tissues of the transgenic mice and an impairment of catecholamine metabolism in the tissues. Targeting of the peripheral catecholaminergic cells resulted in severe and progressive phenotypic abnormalities mainly characterized by cardiac dysfunction, hypoactivity, and hypothermia, which explain development of autonomic neuropathy. Our IMCT strategy is useful for elucidating the involvement of different neuronal types and their interactions in the development and symptom of autonomic disorders.
AB - Autonomic neuropathy in several neurodegenerative disorders results from disturbance in physiological functions of different cell types in the central and peripheral nervous systems. For a clearer understanding of the etiology and pathogenesis of the autonomic disorders it is necessary to create animal models in which degeneration of the causative neuronal types can be induced. Immunotoxin-mediated cell targeting (IMCT) is a novel transgenic mouse technology for eliminating selective cell types with the cytotoxic activity of a recombinant immunotoxin anti-Tac(Fv)-PE40. In this study we conditionally disrupted peripheral catecholaminergic cells with IMCT to generate a mouse model developing autonomic failure based on primary defects of the sympathetic nervous system. Transgenic mice expressing human interleukin-2 receptor α subunit under the control of the dopamine β- hydroxylase gene promoter were intravenously treated with a proper dose of anti-Tac(Fv)-PE40. The immunotoxin induced a selective loss of the target cells in peripheral tissues of the transgenic mice and an impairment of catecholamine metabolism in the tissues. Targeting of the peripheral catecholaminergic cells resulted in severe and progressive phenotypic abnormalities mainly characterized by cardiac dysfunction, hypoactivity, and hypothermia, which explain development of autonomic neuropathy. Our IMCT strategy is useful for elucidating the involvement of different neuronal types and their interactions in the development and symptom of autonomic disorders.
KW - Catecholamine metabolism
KW - Cell targeting
KW - Dopamine β- hydroxylase
KW - Recombinant immunotoxin
KW - Sympathetic nervous system
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U2 - 10.1002/(SICI)1097-4547(19980115)51:2<162::AID-JNR5>3.0.CO;2-B
DO - 10.1002/(SICI)1097-4547(19980115)51:2<162::AID-JNR5>3.0.CO;2-B
M3 - Article
C2 - 9469570
AN - SCOPUS:0032518239
SN - 0360-4012
VL - 51
SP - 162
EP - 173
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
IS - 2
ER -