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Examination of Anatomical Features of Retinal Ganglion Cells Under N-methyl-D-aspartic Acid (NMDA)-induced Excitotoxicity
Published on: September 19, 2025
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Translation regulation of ATF4 by the termination complex Hbs1-Pelo is required for visual system development and
Biorxiv : the Preprint Server for Biology
|November 24, 2025
Summary
Loss of HBS1L causes inherited retinal disease by affecting translation of ATF4 in specific eye cells. Restoring ATF4 partially rescues vision defects in models of this condition.
Area of Science:
- Molecular Biology
- Genetics
- Neuroscience
Background:
- Inherited retinal diseases stem from genetic mutations affecting retinal function and causing vision loss.
- HBS1L (translation termination factor) mutations are linked to developmental anomalies, including progressive vision loss.
- The specific mRNA targets and cell types affected by HBS1L deficiency in vision remain unidentified.
Purpose of the Study:
- To identify the mRNA target and affected cell types involved in HBS1L-related inherited retinal disease.
- To elucidate the mechanism by which HBS1L influences vision development and function.
Main Methods:
- Investigated HBS1L homolog (Hbs1) function in Drosophila models and cultured human cells.
- Analyzed Activating Transcription Factor 4 (ATF4) expression and translation reinitiation.
- Utilized electroretinograms (ERGs) to assess vision defects and confocal microscopy for cellular analysis.
Main Results:
- Loss of Hbs1 in Drosophila reduced ATF4 expression, a gene with upstream open reading frames (uORFs).
- HBS1L and Pelota (Pelo) facilitate ATF4 translation reinitiation in human cells.
- Hbs1 depletion in Drosophila lamina neurons caused ERG defects and synaptic vacuolization; ATF4 restoration partially rescued ERG defects.
Conclusions:
- HBS1L-Pelo complex regulates ATF4 translation, likely via translation reinitiation at uORFs.
- Defective HBS1L-Pelo-mediated ATF4 translation in lamina neurons contributes to inherited retinal disease.
- ATF4 is a key mRNA target underlying vision loss in HBS1L deficiency.
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