Deciphering discord: How Drosophila research has enhanced our understanding of the importance of FMRP in different spatial and temporal contexts

Abstract

Fragile X Syndrome (FXS) is the most common heritable form of intellectual impairment as well as the leading monogenetic cause of autism. In addition to its canonical definition as a neurodevelopmental disease, recent findings in the clinic suggest that FXS is a systemic disorder that is characterized by a variety of heterogeneous phenotypes. Efforts to study FXS pathogenesis have been aided by the development and characterization of animal models of the disease. Research efforts in Drosophila melanogaster have revealed key insights into the mechanistic underpinnings of FXS. While much remains unknown, it is increasingly apparent that FXS involves a myriad of spatially and temporally specific alterations in cellular function. Consequently, the literature is filled with numerous discordant findings. Researchers and clinicians alike must be cognizant of this dissonance, as it will likely be important for the design of preclinical studies to assess the efficacy of therapeutic strategies to improve the lives of FXS patients.

Multifarious Functions of the Fragile X Mental Retardation Protein

“…FMRP functions as a master regulator of activity-dependent neurodevelopment, with null mutants manifesting hyperexcitability and reduced activity-dependent modulation of synapse maturation, refinement and plasticity [1]. FMRP is canonically defined as an mRNA-binding translational repressor, with a broad but largely indeterminate range of transcript targets [2], but the scope of FMRP genetic functions continues to explode (Table 1). From the cytosol, FMRP is classically described to shuttle to/from the nucleus, with a recent Drosophila study mapping a novel C-terminus mutation to this nuclear export function [3].…”

“…In the mouse FXS model, recent work shows FMRP loss changes cell differentiation kinetics for both neurons and glia (Table 1) [14], and astrocyte-specific FMRP knockout in mice increases neuronal dendritic spine density similar to the global FXS condition [15]. Within neurons in all model systems, the soma contains the vast majority of FMRP, yet the lion’s share of research and discussion focuses on local FMRP functions at the synapse [2,16–19]. Most study postsynaptic mechanisms, but there appears to be at least as many presynaptic mRNA targets and presynaptic defects in mutants [2,16,20,21].…”

“…Within neurons in all model systems, the soma contains the vast majority of FMRP, yet the lion’s share of research and discussion focuses on local FMRP functions at the synapse [2,16–19]. Most study postsynaptic mechanisms, but there appears to be at least as many presynaptic mRNA targets and presynaptic defects in mutants [2,16,20,21]. Yet another long-term debate concerns the timing of FMRP requirements [2].…”

“…Most study postsynaptic mechanisms, but there appears to be at least as many presynaptic mRNA targets and presynaptic defects in mutants [2,16,20,21]. Yet another long-term debate concerns the timing of FMRP requirements [2]. Although FXS defects persist throughout life in both patients and animal models, this does not necessarily require continuous, maintained FMRP function [22–24].…”

“…The critical question of FMRP roles during neurodevelopment versus maturity is centrally important for determining optimal FXS treatment strategies [1,2,21,25,26]. Recent FXS clinical trials have been greatly disappointing, but this may be in large part due to targeting adult patients [21].…”