Drosophilafragile X mental retardation protein developmentally regulates activity-dependent axon pruning

Abstract

Fragile X Syndrome (FraX) is a broad-spectrum neurological disorder with symptoms ranging from hyperexcitability to mental retardation and autism. Loss of the fragile X mental retardation 1 (fmr1) gene product, the mRNA-binding translational regulator FMRP, causes structural over-elaboration of dendritic and axonal processes, as well as functional alterations in synaptic plasticity at maturity. It is unclear, however, whether FraX is primarily a disease of development, a disease of plasticity or both: a distinction that is vital for engineering intervention strategies. To address this crucial issue, we have used the Drosophila FraX model to investigate the developmental function of Drosophila FMRP (dFMRP). dFMRP expression and regulation of chickadee/profilin coincides with a transient window of late brain development. During this time, dFMRP is positively regulated by sensory input activity, and is required to limit axon growth and for efficient activity-dependent pruning of axon branches in the Mushroom Body learning/memory center. These results demonstrate that dFMRP has a primary role in activity-dependent neural circuit refinement during late brain development.

FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control

“…Prior studies at the Drosophila neuromuscular junction have strongly indicated presynaptic functions for dFmr1 and translational control but have also pointed to their significant postsynaptic involvement in neuromuscular junction maturation, growth, and plasticity (75,76). More direct studies of experienceinduced long-term plasticity have been performed in the context of Drosophila olfactory associative memory, wherein a specific dFmr1 isoform in particular and translational control in general are necessary for long-term forms of memory (16,44).…”

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

“…These reports have provided considerable insight into the mechanism that might underlie abnormal synapse development and dendritic spine morphology in FXS. In Drosophila, FMRP is essential for synapse formation and experience-dependent axonal pruning during development (Gatto and Broadie, 2008;Tessier and Broadie, 2008). Studies in Fmr1 KO mice have further revealed that FMRP regulates protein synthesis-dependent axon pruning, dendritic spine elimination, and actin-dependent stabilization of spines.…”

“…Evidence from FXS Drosophila and mouse models suggests that calcium signaling is disturbed in the absence of FMRP, which could partially account for defects in neuronal network formation (Meredith et al, 2007;Tessier and Broadie, 2008). Furthermore, a recent report proposed a role for FMRP in retinoic acid-mediated homeostatic plasticity, an important signaling pathway regulating network activity (Soden and Chen, 2010).…”

Guidance Molecules in Axon Pruning and Cell Death

“…Various intrinsic factors have been identified to regulate the pruning of axons and dendrites in Drosophila. These include the ubiquitin-proteosome system (Kuo et al 2006;Watts et al 2003), regulators of cytoskeletal dynamics (Billuart et al 2001;Lee et al 2009), caspase activities , transcription factors (Parrish et al 2007), RNAbinding proteins (Hoopfer et al 2008), proteins that hold sister chromatids together (Schuldiner et al 2008), and the FMRP protein disrupted in fragile X mental retardation (Tessier and Broadie 2008). Notably, molecular mechanisms involved in axon pruning in Drosophila share similarities with Wallerian degeneration in vertebrates.…”