Dysregulation of BMP, Wnt, and Insulin Signaling in Fragile X Syndrome

Abstract

Drosophila models of neurological disease contribute tremendously to research progress due to the high conservation of human disease genes, the powerful and sophisticated genetic toolkit, and the rapid generation time. Fragile X syndrome (FXS) is the most prevalent heritable cause of intellectual disability and autism spectrum disorders, and the Drosophila FXS disease model has been critical for the genetic screening discovery of new intercellular secretion mechanisms. Here, we focus on the roles of three major signaling pathways: BMP, Wnt, and insulin-like peptides. We present Drosophila FXS model defects compared to mouse models in stem cells/embryos, the glutamatergic neuromuscular junction (NMJ) synapse model, and the developing adult brain. All three of these secreted signaling pathways are strikingly altered in FXS disease models, giving new mechanistic insights into impaired cellular outcomes and neurological phenotypes. Drosophila provides a powerful genetic screening platform to expand understanding of these secretory mechanisms and to test cellular roles in both peripheral and central nervous systems. The studies demonstrate the importance of exploring broad genetic interactions and unexpected regulatory mechanisms. We discuss a number of research avenues to pursue BMP, Wnt, and insulin signaling in future FXS investigations and the development of potential therapeutics.

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

“…Previous genetic studies have shown that PDF-Tri neuron removal over the first 5 d in the early juvenile brain requires phagocytosis clearance by two cooperating glial subclasses ( 16 , 19 ). To begin to dissect this mechanism further, we imaged interactions between glia and neurons early and late in this clearance process at 1 day posteclosion (dpe) and 5 dpe.…”

“…Since this conclusion is opposite to expectations, a second FMRP-pMad interactive pathway was suspected to result in the dfmr1 RNAi phenocopy. As both FMRP and pMad interact with insulin receptor (InR) signaling ( 19 , 20 , 29 ), we therefore next focused on testing InR dysregulation in neuronal dfmr1 and mad RNAi conditions. With qPCR assays, InR expression is oppositely modulated by neuronal dfmr1 and mad RNAi ( Fig.…”

“…In parallel, the neuronal insulin receptor (InR) regulates pAkt signaling in a second intersecting cascade controlling the neuronal clearance mechanism. This bone morphogenic protein (BMP) and insulin-like peptide (ILP) neural decision-making network ( 19 ) controls neuron-to-glia communication regulating glial phagocytosis function for targeted neuron removal. Neuronal pretaporter (Prtp) is a ligand for the draper (Drpr) engulfment receptor on glia ( 26 ).…”

“…FMRP regulates bone morphogenic protein (BMP) and insulin-like peptide (ILP) signaling ( 19 ). Activated Drosophila BMP receptors phosphorylate mothers against decapentaplegic (pMad) to control gene transcription, including the insulin receptor (InR) ( 20 , 21 ).…”