The LIM homeodomain transcription factor ISL1 is essential for the different aspects of neuronal development and maintenance. In order to study the role of ISL1 in the auditory system, we generated a transgenic mouse (Tg) expressing Isl1 under the Pax2 promoter control. We previously reported a progressive age-related decline in hearing and abnormalities in the inner ear, medial olivocochlear system, and auditory midbrain of these Tg mice. In this study, we investigated how Isl1 overexpression affects sound processing by the neurons of the inferior colliculus (IC). We recorded extracellular neuronal activity and analyzed the responses of IC neurons to broadband noise, clicks, pure tones, two-tone stimulation and frequency-modulated sounds. We found that Tg animals showed a higher inhibition as displayed by two-tone stimulation; they exhibited a wider dynamic range, lower spontaneous firing rate, longer first spike latency and, in the processing of frequency modulated sounds, showed a prevalence of high-frequency inhibition. Functional changes were accompanied by a decreased number of calretinin and parvalbumin positive neurons, and an increased expression of vesicular GABA/glycine transporter and calbindin in the IC of Tg mice, compared to wild type animals. The results further characterize abnormal sound processing in the IC of Tg mice and demonstrate that major changes occur on the side of inhibition.

• Klíčová slova
• auditory system, inferior colliculus, inhibition, sound processing, transcription factor ISL1,
• MeSH
• colliculus inferior metabolismus   fyziologie   MeSH
• exprese genu genetika   MeSH
• lidé MeSH
• mozek fyziologie   MeSH
• myši transgenní MeSH
• myši MeSH
• neurony fyziologie   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• proteiny s homeodoménou LIM genetika   metabolismus   MeSH
• sluch MeSH
• sluchová percepce genetika   fyziologie   MeSH
• sluchové kmenové evokované potenciály fyziologie   MeSH
• sluchový práh fyziologie   MeSH
• transkripční faktor PAX2 genetika   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• insulin gene enhancer binding protein Isl-1 MeSH Prohlížeč
• PAX2 protein, human MeSH Prohlížeč
• Pax2 protein, mouse MeSH Prohlížeč
• proteiny s homeodoménou LIM MeSH
• transkripční faktor PAX2 MeSH
• transkripční faktory MeSH

Rodents are characterized by continuously renewing incisors whose growth is fueled by epithelial and mesenchymal stem cells housed in the proximal compartments of the tooth. The epithelial stem cells reside in structures known as the labial (toward the lip) and lingual (toward the tongue) cervical loops (laCL and liCL, respectively). An important feature of the rodent incisor is that enamel, the outer, highly mineralized layer, is asymmetrically distributed, because it is normally generated by the laCL but not the liCL. Here, we show that epithelial-specific deletion of the transcription factor Islet1 (Isl1) is sufficient to drive formation of ectopic enamel by the liCL stem cells, and also that it leads to production of altered enamel on the labial surface. Molecular analyses of developing and adult incisors revealed that epithelial deletion of Isl1 affected multiple, major pathways: Bmp (bone morphogenetic protein), Hh (hedgehog), Fgf (fibroblast growth factor), and Notch signaling were upregulated and associated with liCL-generated ectopic enamel; on the labial side, upregulation of Bmp and Fgf signaling, and downregulation of Shh were associated with premature enamel formation. Transcriptome profiling studies identified a suite of differentially regulated genes in developing Isl1 mutant incisors. Our studies demonstrate that ISL1 plays a central role in proper patterning of stem cell-derived enamel in the incisor and indicate that this factor is an important upstream regulator of signaling pathways during tooth development and renewal. © 2017 American Society for Bone and Mineral Research.

• Klíčová slova
• AMELOGENESIS, ECTOPIC ENAMEL, ISL1, MOUSE INCISOR, TOOTH DEVELOPMENT,
• MeSH
• delece genu MeSH
• epitel embryologie   metabolismus   MeSH
• fyziologická kalcifikace * MeSH
• mandibula metabolismus   MeSH
• mutace genetika   MeSH
• myši MeSH
• orgánová specificita MeSH
• proteiny s homeodoménou LIM genetika   metabolismus   MeSH
• řezáky embryologie   metabolismus   MeSH
• rozvržení tělního plánu * MeSH
• sekvenční analýza RNA MeSH
• signální transdukce MeSH
• stanovení celkové genové exprese MeSH
• transkripční faktory genetika   metabolismus   MeSH
• vývojová regulace genové exprese MeSH
• zubní sklovina embryologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• insulin gene enhancer binding protein Isl-1 MeSH Prohlížeč
• proteiny s homeodoménou LIM MeSH
• transkripční faktory MeSH

The development, maturation, and maintenance of the inner ear are governed by temporal and spatial expression cascades of transcription factors that form a gene regulatory network. ISLET1 (ISL1) may be one of the major players in this cascade, and in order to study its role in the regulation of inner ear development, we produced a transgenic mouse overexpressing Isl1 under the Pax2 promoter. Pax2-regulated ISL1 overexpression increases the embryonic ISL1(+) domain and induces accelerated nerve fiber extension and branching in E12.5 embryos. Despite these gains in early development, the overexpression of ISL1 impairs the maintenance and function of hair cells of the organ of Corti. Mutant mice exhibit hyperactivity, circling behavior, and progressive age-related decline in hearing functions, which is reflected in reduced otoacoustic emissions (DPOAEs) followed by elevated hearing thresholds. The reduction of the amplitude of DPOAEs in transgenic mice was first detected at 1 month of age. By 6-9 months of age, DPOAEs completely disappeared, suggesting a functional inefficiency of outer hair cells (OHCs). The timing of DPOAE reduction coincides with the onset of the deterioration of cochlear efferent terminals. In contrast to these effects on efferents, we only found a moderate loss of OHCs and spiral ganglion neurons. For the first time, our results show that the genetic alteration of the medial olivocochlear (MOC) efferent system induces an early onset of age-related hearing loss. Thus, the neurodegeneration of the MOC system could be a contributing factor to the pathology of age-related hearing loss.

• Klíčová slova
• Age-related hearing loss, Islet1 transcription factor, Medial olivocochlear efferent system, Outer hair cells, Transgenic mouse,
• MeSH
• analýza přežití MeSH
• embryo savčí metabolismus   patologie   MeSH
• ganglion spirale patologie   MeSH
• kochlea inervace   patologie   patofyziologie   MeSH
• messenger RNA genetika   metabolismus   MeSH
• molekulární motory metabolismus   MeSH
• myši transgenní MeSH
• nedoslýchavost patologie   patofyziologie   MeSH
• neurony eferentní MeSH
• otoakustické emise spontánní MeSH
• počet buněk MeSH
• proteiny s homeodoménou LIM metabolismus   MeSH
• sluchový práh MeSH
• stárnutí patologie   MeSH
• transkripční faktor PAX2 metabolismus   MeSH
• transkripční faktory metabolismus   MeSH
• vnější vláskové buňky patologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• insulin gene enhancer binding protein Isl-1 MeSH Prohlížeč
• messenger RNA MeSH
• molekulární motory MeSH
• Pax2 protein, mouse MeSH Prohlížeč
• Pres protein, mouse MeSH Prohlížeč
• proteiny s homeodoménou LIM MeSH
• transkripční faktor PAX2 MeSH
• transkripční faktory MeSH