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.
Highlights
The vestibular system of the ear provides a major input for balance [1]
We present data showing that Isl1 overexpression causes some aberrant development of the vestibular system and the central nervous system, in particular the cerebellum, which may relate to hyperactivity
We present data showing that Isl1 overexpression causes molecular and morphological changes in the cerebellum and vestibular system that may cause hyperactivity, including circling behavior of Tg+/− mice
Summary
The vestibular system of the ear provides a major input for balance [1]. Hair cells located within the five vestibular epithelia (the utricle, the saccule, and the lateral, superior, and posterior semicircular canal cristae) receive and convert stimuli in the three cardinal planes into electric signals [2]. The cerebellum receives proprioceptive input [5] and is part of a motor control loop to modify cortical signals for smooth, integrated movements [6] of the extraocular and skeletal muscles [7, 8]. The vestibular and proprioceptive signals are further processed and integrated together with other sensory, motor, and associative signals in the striatum, a central brain area for motor control (reviewed in [9]).
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