PTEN Regulates Alternative Splicing of ASD-Linked Transcripts in Neurons
Overview
PTEN deficiency in primary cortical neurons leads to widespread mis-splicing of transcripts, particularly affecting genes associated with autism spectrum disorder (ASD). This splicing dysregulation involves altered exon inclusion/exclusion patterns linked to synaptic and gene expression regulatory functions, independent of the canonical PI3K/mTOR pathway.
Background
PTEN is a tumor suppressor that antagonizes the PI3K/AKT/mTOR signaling pathway and is mutated in 10%–20% of individuals with ASD exhibiting macrocephaly. While hyperactive mTOR signaling contributes to neuronal abnormalities in PTEN-ASD, PTEN also regulates gene transcription and pre-mRNA splicing independently of this pathway. Alternative splicing defects are a hallmark of ASD brains, but the molecular mechanisms remain unclear. This study investigates how PTEN loss affects splicing in primary cortical neurons and its implications for ASD.
Data Highlights
RNA sequencing of Pten-deficient primary cortical mouse neurons revealed global mis-splicing of transcripts, with a developmental regulation pattern. Exons with strong 3′ splice sites were more frequently excluded, while those with weak splice sites were more often included. Many mis-spliced transcripts correspond to known ASD susceptibility genes involved in synaptic function and gene expression regulation.
Key Findings
PTEN deficiency causes widespread alternative splicing alterations in primary cortical neurons.
Mis-spliced transcripts cluster in synaptic and gene expression regulatory pathways relevant to ASD.
Exons with strong 3′ splice sites are preferentially excluded in PTEN-deficient neurons.
Many affected transcripts are established ASD risk genes, indicating multifactorial dysregulation.
PTEN interacts with spliceosome components such as U2AF65, influencing splicing independently of PI3K/mTOR signaling.
Clinical Implications
These findings suggest that PTEN mutations contribute to ASD pathogenesis not only through mTOR pathway dysregulation but also via altered RNA splicing of critical neuronal genes. Therapeutic strategies targeting splicing regulation or spliceosome function may complement approaches aimed at mTOR signaling in PTEN-associated ASD. Understanding PTEN's role in splicing could improve molecular diagnosis and personalized interventions for ASD patients with PTEN mutations.
Conclusion
PTEN loss in neurons leads to aberrant alternative splicing of ASD-linked genes, highlighting a multifactorial mechanism underlying PTEN-associated autism spectrum disorder. This expands the understanding of PTEN's role beyond mTOR regulation to include critical control of neuronal transcript splicing.
References
PTEN Modulates Alternative Splicing of Transcripts Linked to Autism Spectrum Disorder in Primary Neuronal Cells
