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

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 <i>Drosophila fragile X mental retardation 1</i> (<i>dfmr1</i>) elevates <i>mad</i> transcript levels and increases pMad signaling. Neuronal <i>dfmr1</i> and <i>mad</i> 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 <i>mad</i> RNAi background restores normal remodeling. Consistently, neuronal <i>dfmr1</i> and <i>mad</i> RNAi both decrease Prtp levels, whereas neuronal <i>InR</i> and <i>akt</i> 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 <i>dfmr1</i> and <i>mad</i> and <i>akt</i> 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.