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Updated: May 7, 2026
Dissecting Cell-Autonomous Function of Fragile X Mental Retardation Protein in an Auditory Circuit by In Ovo Electroporation
Published on: July 6, 2022
Fragile X mental retardation protein regulates trans-synaptic signaling in Drosophila
Samuel H Friedman1, Neil Dani, Emma Rushton
1Department of Biological Sciences, Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37212, USA.
Abstract:
Fragile X syndrome (FXS), the most common inherited determinant of intellectual disability and autism spectrum disorders, is caused by loss of the fragile X mental retardation 1 (FMR1) gene product (FMRP), an mRNA-binding translational repressor. A number of conserved FMRP targets have been identified in the well-characterized Drosophila FXS disease model, but FMRP is highly pleiotropic in function and the full spectrum of FMRP targets has yet to be revealed. In this study, screens for upregulated neural proteins in Drosophila fmr1 (dfmr1) null mutants reveal strong elevation of two synaptic heparan sulfate proteoglycans (HSPGs): GPI-anchored glypican Dally-like protein (Dlp) and transmembrane Syndecan (Sdc). Our recent work has shown that Dlp and Sdc act as co-receptors regulating extracellular ligands upstream of intracellular signal transduction in multiple trans-synaptic pathways that drive synaptogenesis. Consistently, dfmr1 null synapses exhibit altered WNT signaling, with changes in both Wingless (Wg) ligand abundance and downstream Frizzled-2 (Fz2) receptor C-terminal nuclear import. Similarly, a parallel anterograde signaling ligand, Jelly belly (Jeb), and downstream ERK phosphorylation (dpERK) are depressed at dfmr1 null synapses. In contrast, the retrograde BMP ligand Glass bottom boat (Gbb) and downstream signaling via phosphorylation of the transcription factor MAD (pMAD) seem not to be affected. To determine whether HSPG upregulation is causative for synaptogenic defects, HSPGs were genetically reduced to control levels in the dfmr1 null background. HSPG correction restored both (1) Wg and Jeb trans-synaptic signaling, and (2) synaptic architecture and transmission strength back to wild-type levels. Taken together, these data suggest that FMRP negatively regulates HSPG co-receptors controlling trans-synaptic signaling during synaptogenesis, and that loss of this regulation causes synaptic structure and function defects characterizing the FXS disease state.
Insights
Fragile X syndrome (FXS) results from loss of FMRP, leading to elevated synaptic heparan sulfate proteoglycans (HSPGs). Restoring HSPG levels corrects synaptic signaling and architecture defects in the FXS disease model.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Fragile X syndrome (FXS) is a leading inherited cause of intellectual disability and autism spectrum disorders.
- FXS arises from the loss of fragile X mental retardation 1 (FMR1) gene product (FMRP), an mRNA-binding translational repressor.
- The full spectrum of FMRP targets and their roles in FXS pathogenesis remain incompletely understood.
Purpose of the Study:
- To identify novel FMRP targets and elucidate their role in FXS pathophysiology.
- To investigate the function of synaptic heparan sulfate proteoglycans (HSPGs) in the Drosophila FXS model.
- To determine if HSPG dysregulation contributes to synaptic defects observed in FXS.
Main Methods:
- Utilized Drosophila melanogaster as a model organism for FXS research.
- Conducted screens for upregulated neural proteins in fmr1 null mutants.
- Employed genetic manipulation to reduce HSPG levels in dfmr1 null mutants and assessed downstream signaling pathways.
Main Results:
- Screens revealed significant upregulation of two synaptic HSPGs, Dally-like protein (Dlp) and Syndecan (Sdc), in dfmr1 null mutants.
- dfmr1 null synapses showed altered WNT signaling (Wingless ligand abundance and Frizzled-2 receptor nuclear import) and depressed anterograde signaling (Jelly belly ligand and dpERK phosphorylation).
- Genetic reduction of HSPGs in dfmr1 null mutants restored WNT and Jelly belly signaling, synaptic architecture, and transmission strength to wild-type levels.
Conclusions:
- FMRP acts as a negative regulator of synaptic HSPGs that control trans-synaptic signaling during synaptogenesis.
- Upregulation of HSPGs due to FMRP loss contributes to the synaptic structure and function defects characteristic of FXS.
- Targeting HSPG regulation may offer a therapeutic strategy for FXS.
