The human FMR1 gene is implicated in fragile X syndrome and fragile X tremor/ataxia syndrome. Fragile X syndrome has been extensively studied in Drosophila models; see the human disease model report 'fragile X syndrome' (FBhh0000136). This syndrome has variable phenotypes, which usually includes moderate to severe intellectual disability and may include autistic behaviors, obesity, and sleep disturbances. There is a single fly ortholog of FMR1, Dmel\Fmr1, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Fmr1 is also orthologous to two additional human genes, FXR1 and FXR2.
UAS constructs of the human Hsap\FMR1 have been introduced into flies, but have not been characterized in the context of this disease model.
In flies, expression of Dmel\Fmr1 in the insulin-producing cells (IPCs) of the brain is sufficient to restore normal circadian behavior and to rescue the memory deficit phenotype of animals carrying loss-of-function Fmr1 mutations. This was an unexpected discovery: after establishing that pan-neuronal expression of Fmr1 rescues the Fmr1 circadian phenotypes, expression in subsets of neurons was tested; expression in neurons known to affect circadian behavior has no effect on the circadian phenotypes of Fmr1, however, expression in the IPC cells (using an Ilp2 driver) results in rescue of the circadian phenotypes. Memory defects are also ameliorated.
Markers of insulin signaling (IS) are increased in the brains of flies carrying loss-of-function Fmr1 mutations. Reducing insulin signaling in Fmr1 mutant flies, either through the targeted expression of Fmr1 in the insulin-producing cells or through genetic reduction of IS, rescues both memory and circadian rhythmicity defects. Treatment of Fmr1 mutant animals with the insulin-normalizing drug metformin results in partial rescue of the short-term memory defect.
Based on experiments modulating expression in Drosophila intestinal stem cells (ISCs), Dmel\Fmr1 is postulated to control the insulin sensitivity of intestinal progenitor cells, impacting the process that underlies the adaptive growth of the adult intestine in response to nutrition.
Most amorphic mutations of Dmel\Fmr1 are semi-lethal, with the majority of animals dying during the pupal stage; effects can be studied in larvae and in surviving adults. Adults exhibit neurological phenotypes such as memory defective, locomotor rhythm defective, courtship behavior defective, and neuroanatomy defective; male sterility or semi-sterility is observed for several alleles; sleep and circadian defects have been observed. Extensive physical and genetic interactions of Dmel\Fmr1 have been described; see below and in the gene report for Fmr1.
[updated Jan. 2019 by FlyBase; FBrf0222196]
The FMR1 protein is part of an RNA-binding complex that binds to the mRNA cap and mediates translational repression; may also play a role in intracellular transport of mRNA from the nucleus to the cytoplasm. [UniProt:Q06787; 2016.01.15]
FMR1 encodes a multifunctional polyribosome-associated RNA-binding protein that plays a central role in neuronal development and synaptic plasticity through the regulation of alternative mRNA splicing, mRNA stability, mRNA dendritic transport and postsynaptic local protein synthesis of a subset of mRNAs. [Gene Cards, FMR1; 2019.01.14]
Many to one: 3 human to 1 Drosophila. Three human genes, FMR1, FXR1 and FXR2, are orthologous to the fly gene Dmel\Fmr1.
High-scoring ortholog of human gene FMR1, FXR1 and FXR2 (1 Drosophila to 3 human). Dmel\Fmr1 shares 36-38% identity and 51-53% similarity with each of the 3 human genes.