Behavioral abnormalities of Zic1 and Zic2 mutant mice: implications as models for human neurological disorders.
Zic1 and Zic2 encode closely related zinc finger proteins expressed in dorsal neural tube and its derivatives. In previous studies, we showed that the homozygous Zic1 null mutation (Zic1-/-) results in cerebellar malformation with severe ataxia and that holoprosencephaly and spina bifida occur in homozygotes for Zic2 knockdown mutation (Zic2kd/kd). Since human ZIC2 haploinsufficiency is a cause of holoprosencephaly, the Zic2kd/kd mice are regarded as an animal model for holoprosencephaly in humans. In this study, the behavioral characteristics of the Zic1 and Zic2 mutant mice were investigated in heterozygotes (Zic1-/+ or Zic2kd/+), and significant abnormalities were found in the hanging, spontaneous locomotor activity, stationary rod (Zic1-/+), acoustic startle response, and prepulse inhibition tests (Zic2kd/+). The abnormalities in the Zic1-/+ mice may be explained in part by the hypotonia caused by hypoplasia of the cerebellar anterior vermis, and these mice are regarded as a model of Joubert syndrome. In contrast, the sensorimotor gating abnormality in the Zic2kd/+ mice may be attributable to the presumed abnormality in the dorsomedial forebrain, which was strongly affected in the Zic2kd/kd mice. Zic2kd/+ mice can serve as a model for diseases involving sensorimotor gating abnormalities, such as schizophrenia.
Ogura
H
H
Tsukuba Research Laboratories, Eisai Co. Ltd., Tsukuba-shi, Ibaraki, Japan.
Aruga
J
J
Mikoshiba
K
K
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000002:abnormalities; D004195:Disease Models, Animal; D016142:Holoprosencephaly / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants / Q000235:genetics*; D008957:Models, Genetic; D009123:Muscle Hypotonia / Q000235:genetics*; D009687:Nuclear Proteins; D012559:Schizophrenia / Q000235:genetics*; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*
D009687:Nuclear Proteins; D014157:Transcription Factors; C492123:ZIC1 protein, human; C491812:ZIC2 protein, human; C492122:Zic1 protein, mouse; C491811:Zic2 protein, mouse