Neuronal fragile X mental retardation protein activates glial insulin receptor mediated PDF-Tri neuron developmental clearance

Dominic J Vita,Cole J Meier,Kendal Broadie

doi:10.1038/s41467-021-21429-4

Abstract

Glia engulf and phagocytose neurons during neural circuit developmental remodeling. Disrupting this pruning process contributes to Fragile X syndrome (FXS), a leading cause of intellectual disability and autism spectrum disorder in mammals. Utilizing a Drosophila FXS model central brain circuit, we identify two glial classes responsible for Draper-dependent elimination of developmentally transient PDF-Tri neurons. We find that neuronal Fragile X Mental Retardation Protein (FMRP) drives insulin receptor activation in glia, promotes glial Draper engulfment receptor expression, and negatively regulates membrane-molding ESCRT-III Shrub function during PDF-Tri neuron clearance during neurodevelopment in Drosophila. In this context, we demonstrate genetic interactions between FMRP and insulin receptor signaling, FMRP and Draper, and FMRP and Shrub in PDF-Tri neuron elimination. We show that FMRP is required within neurons, not glia, for glial engulfment, indicating FMRP-dependent neuron-to-glia signaling mediates neuronal clearance. We conclude neuronal FMRP drives glial insulin receptor activation to facilitate Draper- and Shrub-dependent neuronal clearance during neurodevelopment in Drosophila.

Highlights

Glia engulf and phagocytose neurons during neural circuit developmental remodeling
We find that Fragile X Mental Retardation Protein (FMRP) is required only in neurons, not glia, and acts to regulate intercellular signaling that activates glial insulin receptors to initiate the developmental elimination of peptide-dispersing factor tritocerebrum (PDF-Tri) neurons
We show that FMRPdependent regulation of membrane-molding ESCRT-III Shrub is required, with correction of Shrub levels reducing the inappropriate PDF-Tri neuron retention in the Fragile X syndrome (FXS) disease model

Summary

Introduction

Glia engulf and phagocytose neurons during neural circuit developmental remodeling. Disrupting this pruning process contributes to Fragile X syndrome (FXS), a leading cause of intellectual disability and autism spectrum disorder in mammals. We find that neuronal Fragile X Mental Retardation Protein (FMRP) drives insulin receptor activation in glia, promotes glial Draper engulfment receptor expression, and negatively regulates membrane-molding ESCRTIII Shrub function during PDF-Tri neuron clearance during neurodevelopment in Drosophila. Glia phagocytose neurons in the developing mammalian dorsal root ganglia[12], and similar glial phagocytic activity occurs within the developing Drosophila nervous system[13,14,15,16,17] It is through such glial elimination that the developing brain sculpts the neural circuitry, facilitating optimized function and behavioral output. Shrub/Chmp[4] is known to pinch neuronal membranes to fragment their processes during neuronal clearance[30] Based on these combined studies, we hypothesized glial phagocytic defects in the Drosophila FXS disease model. The engulfment receptor Draper[33]

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Conclusion