title: Pax2-Islet1 Transgenic Mice Are Hyperactive and Have Altered Cerebellar Foliation.
abstract: The programming of cell fate by transcription factors requires precise regulation of their time and level of expression. The LIM-homeodomain transcription factor Islet1 (Isl1) is involved in cell-fate specification of motor neurons, and it may play a similar role in the inner ear. In order to study its role in the regulation of vestibulo-motor development, we investigated a transgenic mouse expressing Isl1 under the Pax2 promoter control (Tg+/-). The transgenic mice show altered level, time, and place of expression of Isl1 but are viable. However, Tg+/-mice exhibit hyperactivity, including circling behavior, and progressive age-related decline in hearing, which has been reported previously. Here, we describe the molecular and morphological changes in the cerebellum and vestibular system that may cause the hyperactivity of Tg+/-mice. The transgene altered the formation of folia in the cerebellum, the distribution of calretinin labeled unipolar brush cells, and reduced the size of the cerebellum, inferior colliculus, and saccule. Age-related progressive reduction of calbindin expression was detected in Purkinje cells in the transgenic cerebella. The hyperactivity of Tg+/-mice is reduced upon the administration of picrotoxin, a non-competitive channel blocker for the γ-aminobutyric acid (GABA) receptor chloride channels. This suggests that the overexpression of Isl1 significantly affects the functions of GABAergic neurons. We demonstrate that the overexpression of Isl1 affects the development and function of the cerebello-vestibular system, resulting in hyperactivity.
authors: Institute of Biotechnology CAS, Prumyslova 595, Vestec, Prague-West District, 25242, Czech Republic.
authors: Romana
authors: R
authors: Bohuslavova
authors: Institute of Biotechnology CAS, Prumyslova 595, Vestec, Prague-West District, 25242, Czech Republic.
authors: Nicole
authors: N
authors: Dodd
authors: Institute of Biotechnology CAS, Prumyslova 595, Vestec, Prague-West District, 25242, Czech Republic.
authors: Iva
authors: I
authors: Macova
authors: Institute of Experimental Medicine CAS, Prague, Czech Republic.
authors: Tetyana
authors: T
authors: Chumak
authors: Institute of Physiology CAS, Prague, Czech Republic.
authors: Martin
authors: M
authors: Horak
authors: Institute of Experimental Medicine CAS, Prague, Czech Republic.
authors: Josef
authors: J
authors: Syka
authors: Department of Biology, University of Iowa, Iowa City, IA, USA.
authors: Bernd
authors: B
authors: Fritzsch
authors: Institute of Biotechnology CAS, Prumyslova 595, Vestec, Prague-West District, 25242, Czech Republic. gpavlinkova@ibt.cas.cz.
authors: Gabriela
authors: G
authors: Pavlinkova
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006948:Hyperkinesis / Q000378:metabolism* / Q000473:pathology*; D060850:LIM-Homeodomain Proteins / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051762:PAX2 Transcription Factor / Q000096:biosynthesis*; D014157:Transcription Factors / Q000096:biosynthesis*; D014722:Vestibule, Labyrinth / Q000378:metabolism / Q000473:pathology
chemical_list: D060850:LIM-Homeodomain Proteins; D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1
keywords: Age-related deterioration of Purkinje cells; Attention deficit hyperactivity disorder; Calcium homeostasis; Cerebellum; Foliation defects; GABA signaling; Hyperactivity; Islet1 transcription factor; Purkinje cells; Transgenic mouse; Vestibular system