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Analysis of Translation in the Developing Mouse Brain using Polysome Profiling
Published on: May 22, 2021
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Differential expression of paralog RNA binding proteins establishes a dynamic splicing program required for normal
Eleonora Cesari1,2, Donatella Farini3,4, Vanessa Medici1
1Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy.
Nucleic Acids Research
|February 7, 2024
Summary
Sam68 and SLM2 RNA binding proteins (RBPs) control brain development through dynamic splicing. Their opposing expression patterns and redundant functions are crucial for neurogenesis and viability.
Area of Science:
- Neuroscience
- Molecular Biology
- Developmental Biology
Background:
- Sam68 and SLM2 are paralogous RNA binding proteins (RBPs) with similar splicing functions in the cerebral cortex.
- Their distinct roles and regulatory interactions during cortical development remain largely uncharacterized.
Purpose of the Study:
- To investigate the relative functions of Sam68 and SLM2 in cortical development.
- To elucidate the regulatory mechanisms governing their expression patterns and splicing activities.
Main Methods:
- Analysis of Sam68 and SLM2 expression patterns during mouse cortical development.
- Generation and analysis of Sam68:Slm2 double knockout (Sam68:Slm2dko) mice.
- Exon-level splicing analysis in wild-type and knockout cortices.
Main Results:
- Sam68 and SLM2 exhibit opposing developmental expression patterns, with SLM2 hierarchically controlling Sam68 expression.
- Joint depletion of Sam68 and SLM2 affects hundreds of exons, revealing their combined impact on splicing.
- SLM2-regulated exons show dynamic splicing, while Sam68-dependent exons are constitutively spliced; this dynamic pattern is abolished in Sam68:Slm2dko mice.
- Sam68:Slm2dko mice exhibit perinatal lethality with neurogenesis and neuronal differentiation defects, and hydrocephalus, linked to altered splicing.
Conclusions:
- Developmental regulation of Sam68 and SLM2 orchestrates a dynamic splicing program essential for brain development and survival.
- These paralogous RBPs provide a robust, redundant mechanism supporting proper cortical development.
- The study highlights the critical role of coordinated RBP function in ensuring proper brain formation and viability.
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