Drosophila DFMR1 Interacts with Genes of the Lgl-Pathway in the Brain Synaptic Architecture

Abstract

Fragile X syndrome is a genetic neuro-developmental disorder, caused by the transcriptional inactivation of the gene Fmr1(Fragile X mental retardation 1). The lack of its protein product (FMRP) is accompanied by defects in synaptic maturation InroductionFragile X syndrome (Fra X) is a genetic disease and the most common form of mental retardation in human. Its primary cause is the loss of Fragile X mental retardation protein 1(FMRP), when an abnormal CGG-repeat expansion occurs in the promoter region of the gene Fmr1. This event induces transcriptional silencing of the gene (50).The clinical neurological consequences of fmr1 inactivation include mental disability, autism and circadian rhythm disturbances which emphasizes the key role of FMRP in the brain, where it is predominantly expressed (13). FMRP is found mostly in the cytoplasm, but it can shuttle to the nucleus as well (19). It is expressed in the neuronal soma and in the neurites: along the dendrites, close to the dendrite spines, in the axonal growth cones and in the mature axons (19,20,41).Murine and Drosophila models provided further fundamental understanding of the molecular and cellular mechanisms, underlying the disease.FMRP is an mRNA-binding protein, which negatively regulates translation of different neuronal transcripts (25,28,42,49,58). It also functions in the mRNA transport in the neurons (15,18) and in the regulation of the mRNA stability (11, 14, 21, 35, 57, reviewed in 12).Both models confirm the main clinical aspects of FraX -neuronal features: dendrite and axon overgrowth and synaptic changes: increased spine numbers, abnormal synaptic growth, morphology and function, altered synaptic plasticity and circadian rhythms, as well as learning and memory deficits (3,22,33,40). Work on Drosophila has shown that dFMRP is also required for the normal neurite extension, guidance and branching of different neurons throughout the nervous system (16, 36, 34, reviewed in 59).As FMRP is an RNA-binding protein, identifying its target mRNAs is a main point in understanding how this protein regulates the nervous system. By means of different approaches data were obtained on different mRNAs, interacting with FMRP (6,8,9,17,35,48,57). The physiological functions of few of them, though, have been validated in vivo (reviewed in 3, 10).Among the most important mRNA targets of FMRP are: Fmr1 mRNA itself, microtubule associated protein 1b (MAP1b), postsynaptic density protein 95kDa (PSD-95), elongation factor 1a (EF1a), glutamate receptor subunits GluR1 and GluR2, activity-regulated cytoskeletal protein (Arc), tumor suppressor protein Lethal giant larvae (Lgl); translation regulators Dco/Dbt, PABP, Orb2, Rm62 and SmD3 (3,8,24,30,37,49,53,57 Much research has been focused on the role of FMRP as a translational regulator of specific synaptic proteins -presynaptic and postsynaptic (1, 19, 57, reviewed in 40).A group of such important proteins are the scaffolding proteins, belonging to the Lgl-familyLgl, Dlg and Scrib. Scaffolding proteins organize the po...

Over-expression of Hsp83 in grossly depletedhsrωlncRNA background causes synthetic lethality andl(2)glphenocopy inDrosophila

“…8D) is significant. Moreover, dFMRP is also reported to bind with l(2)gl transcripts (Georgieva et al 2012). Therefore, it is likely that altered localization and activities of proteins like dFUS, dFMRP, TDP-43 and other hnRNPs can affect levels of transcripts of genes like l(2)gl etc through reduced transcription and/or reduced stability of the transcripts.…”