Fragile X mental retardation protein coordinates neuron-to-glia communication for clearance of developmentally transient brain neurons

Proc Natl Acad Sci U S A. 2023 Mar 21;120(12):e2216887120. doi: 10.1073/pnas.2216887120. Epub 2023 Mar 15.

Abstract

In the developmental remodeling of brain circuits, neurons are removed by glial phagocytosis to optimize adult behavior. Fragile X mental retardation protein (FMRP) regulates neuron-to-glia signaling to drive glial phagocytosis for targeted neuron pruning. We find that FMRP acts in a mothers against decapentaplegic (Mad)-insulin receptor (InR)-protein kinase B (Akt) pathway to regulate pretaporter (Prtp) and amyloid precursor protein-like (APPL) signals directing this glial clearance. Neuronal RNAi of Drosophila fragile X mental retardation 1 (dfmr1) elevates mad transcript levels and increases pMad signaling. Neuronal dfmr1 and mad RNAi both elevate phospho-protein kinase B (pAkt) and delay neuron removal but cause opposite effects on InR expression. Genetically correcting pAkt levels in the mad RNAi background restores normal remodeling. Consistently, neuronal dfmr1 and mad RNAi both decrease Prtp levels, whereas neuronal InR and akt RNAi increase Prtp levels, indicating FMRP works with pMad and insulin signaling to tightly regulate Prtp signaling and thus control glial phagocytosis for correct circuit remodeling. Neuronal dfmr1 and mad and akt RNAi all decrease APPL levels, with the pathway signaling higher glial endolysosome activity for phagocytosis. These findings reveal a FMRP-dependent control pathway for neuron-to-glia communication in neuronal pruning, identifying potential molecular mechanisms for devising fragile X syndrome treatments.

Keywords: Drosophila; PDF-tri clock neurons; glia; insulin; phagocytosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / metabolism
  • Drosophila / metabolism
  • Drosophila Proteins* / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Syndrome* / metabolism
  • Membrane Proteins / metabolism
  • Nerve Tissue Proteins / metabolism
  • Neuroglia / metabolism
  • Neurons / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism

Substances

  • Appl protein, Drosophila
  • Drosophila Proteins
  • Fragile X Mental Retardation Protein
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-akt