title: Argonaute2 suppresses Drosophila fragile X expression preventing neurogenesis and oogenesis defects.
abstract: Fragile X Syndrome is caused by the silencing of the Fragile X Mental Retardation gene (FMR1). Regulating dosage of FMR1 levels is critical for proper development and function of the nervous system and germ line, but the pathways responsible for maintaining normal expression levels are less clearly defined. Loss of Drosophila Fragile X protein (dFMR1) causes several behavioral and developmental defects in the fly, many of which are analogous to those seen in Fragile X patients. Over-expression of dFMR1 also causes specific neuronal and behavioral abnormalities. We have found that Argonaute2 (Ago2), the core component of the small interfering RNA (siRNA) pathway, regulates dfmr1 expression. Previously, the relationship between dFMR1 and Ago2 was defined by their physical interaction and co-regulation of downstream targets. We have found that Ago2 and dFMR1 are also connected through a regulatory relationship. Ago2 mediated repression of dFMR1 prevents axon growth and branching defects of the Drosophila neuromuscular junction (NMJ). Consequently, the neurogenesis defects in larvae mutant for both dfmr1 and Ago2 mirror those in dfmr1 null mutants. The Ago2 null phenotype at the NMJ is rescued in animals carrying an Ago2 genomic rescue construct. However, animals carrying a mutant Ago2 allele that produces Ago2 with significantly reduced endoribonuclease catalytic activity are normal with respect to the NMJ phenotypes examined. dFMR1 regulation by Ago2 is also observed in the germ line causing a multiple oocyte in a single egg chamber mutant phenotype. We have identified Ago2 as a regulator of dfmr1 expression and have clarified an important developmental role for Ago2 in the nervous system and germ line that requires dfmr1 function.
authors.affiliation: Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Anita S-R
authors.initials: AS
authors.lastname: Pepper
authors.forename: Rebecca W
authors.initials: RW
authors.lastname: Beerman
authors.forename: Balpreet
authors.initials: B
authors.lastname: Bhogal
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Jongens
mesh_terms: D000818:Animals; D060565:Argonaute Proteins; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D009046:Motor Neurons / Q000378:metabolism; D009420:Nervous System / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009866:Oogenesis / Q000502:physiology*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D034743:RNA-Induced Silencing Complex / Q000502:physiology*
chemical_list: D060565:Argonaute Proteins; D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D034741:RNA, Small Interfering; D034743:RNA-Induced Silencing Complex; C433807:AGO2 protein, Drosophila; C467328:FMR1 protein, Drosophila