DNMT3L affects synaptic function and induces neurobehavioral alterations in Drosophila via Sqd

Area of Science:

• Neurobiology
• Genetics
• Molecular Biology

Background:

• Autism spectrum disorder (ASD) frequently co-occurs with Down syndrome (DS), but the underlying molecular links are not well understood.
• DNA methyltransferase 3-like (DNMT3L) is elevated in DS brain tissue and influences neural development.
• The neurobiological roles of the heterogeneous nuclear ribonucleoprotein D (HNRNPD) family remain largely unexplored.

Purpose of the Study:

• To investigate the molecular mechanisms underlying the comorbidity of ASD and DS.
• To identify novel interactions and regulatory pathways involving DNMT3L and HNRNPD in neural development.

Main Methods:

• Generation of Drosophila melanogaster models overexpressing DNMT3L.
• Mass spectrometry to identify DNMT3L binding partners.
• Confirmation of physical interactions and regulatory effects in both Drosophila and mammalian cell lines.

Main Results:

• Identified Squid (Drosophila HNRNPD homolog) as a DNMT3L binding partner.
• Demonstrated that DNMT3L overexpression suppresses Squid function, enhances mRNA stability and expression of fipi (a neural development gene).
• Observed neurobehavioral changes and altered synaptic plasticity in flies, with similar interactions and regulatory effects on NCAM1/2 (fipi homologs) in mammalian cells.

Conclusions:

• Revealed a novel regulatory axis: DNMT3L-Sqd/HNRNPD-fipi/NCAM.
• This pathway provides a molecular basis for understanding ASD and DS comorbidity.
• The findings suggest potential therapeutic targets for treating co-occurring ASD and DS.