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

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 () elevates transcript levels and increases pMad signaling. Neuronal and 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 RNAi background restores normal remodeling. Consistently, neuronal and RNAi both decrease Prtp levels, whereas neuronal and 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 and and 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.