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Abstract
Sensory organs are constantly exposed to physical and chemical stresses that collectively threaten the survival of sensory neurons. Failure to protect stressed neurons leads to age-related loss of neurons and sensory dysfunction in organs in which the supply of new sensory neurons is limited, such as the human auditory system. Transducin β-like protein 1 (TBL1) is a candidate gene for ocular albinism with late-onset sensorineural deafness, a form of X-linked age-related hearing loss. TBL1 encodes an evolutionarily conserved F-box–like and WD40 repeats–containing subunit of the nuclear receptor co-repressor/silencing mediator for retinoid and thyroid hormone receptor and other transcriptional co-repressor complexes. Here we report that a Drosophila homologue of TBL1, Ebi, is required for maintenance of photoreceptor neurons. Loss of ebi function caused late-onset neuronal apoptosis in the retina and increased sensitivity to oxidative stress. Ebi formed a complex with activator protein 1 (AP-1) and was required for repression of Drosophila pro-apoptotic and anti-apoptotic genes expression. These results suggest that Ebi/AP-1 suppresses basal transcription levels of apoptotic genes and thereby protects sensory neurons from degeneration.
Highlights
Exposure to physical and chemical stresses as well as to overstimulation is a major cause of the cell death of sensory neurons and is considered a causative factor for age-related sensory dysfunction, such as age-related hearing loss (ARHL) and age-related macular degeneration (AMD) [1], [2].A large body of evidence suggests that sensory organ defects are elicited by the overproduction of reactive oxygen species (ROS) that form in the sensory organ as a result of these insults, as well as by overstimulation by external stimuli [1], [3]
Transducin b-like protein 1 (TBL1) was originally reported as a homologous molecule of ebi, a downstream component of epidermal growth factor receptor signaling in Drosophila [13]
TBL1 and TBLR1 were shown to act in many aspects of developmental processes by forming a complex with different types of transcription factors, including nuclear receptor molecules and activator protein 1 (AP-1) [9], [12]
Summary
Exposure to physical and chemical stresses as well as to overstimulation is a major cause of the cell death of sensory neurons and is considered a causative factor for age-related sensory dysfunction, such as age-related hearing loss (ARHL) and age-related macular degeneration (AMD) [1], [2]. Quantification of the number of abnormal ommatidia with a loss of rhabdomeres in large ebi2/2 mosaic clones (referred to as ebi2/2 clones) revealed that severe degeneration occurred at 4 weeks after eclosion (Figure 1C–F) [22] These data suggest that ebi itself is required for the long-term survival of sensory cells. Th showed very mild effect on the compound eye phenotype along with ebiDC, it severely enhanced retinal degeneration of ebiDC at the adult onset (Figure 6C and 6D; Figure S5) These results suggest that multiple pro-apoptotic genes might be required for the late-onset degeneration phenotype in ebi mutant. We crossed ebiDC with Jra or hep and found that Jra and hep mutations consistently suppressed the late-onset retinal degenerative phenotype of ebiDC (Figure 6G and 6H) These data suggest that retinal cells survival might be maintained by the activity of the Ebi/AP-1 repressor complex acting downstream of JNK signalling. Light exposure critically affects the onset of retinal degeneration associated with ebi mutants
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