PT  - JOURNAL ARTICLE
AU  - Ethan J. Greenblatt
AU  - Allan C. Spradling
TI  - Fragile X mental retardation protein is a size-dependent translational activator
AID  - 10.1101/257204
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 257204
4099  - http://biorxiv.org/content/early/2018/01/31/257204.short
4100  - http://biorxiv.org/content/early/2018/01/31/257204.full
AB  - FMR1 enhances translation of large neural/oocyte proteinsMutations in the highly conserved Fragile X mental retardation gene (Fmr1) cause the most common inherited human intellectual disability/autism spectrum disorder. Fmr1 is also needed for ovarian follicle development, and lesions are the largest genetic cause of premature ovarian failure (POF). FMR1 associates with ribosomes and is thought to repress translation, but identifying functional targets has been difficult. We analyzed FMR1’s role in quiescent Drosophila oocytes stored prior to ovulation, cells that depend entirely on translation of stored mRNA. Ribosome profiling revealed that in quiescent oocytes FMR1 stimulates the translation of large proteins, including at least twelve proteins whose human homologs are associated with dominant intellectual disability disorders, and 25 others associated with neural dysfunction. Knockdown of Fmr1 in unstored oocytes did not affect embryo development, but more than 50% of embryos derived from stored oocytes lacking FMR1 developed severe neural defects. Fmr1’s previously unappreciated role promoting the translation of large proteins from stored mRNAs in oocytes and neurons may underlie POF as well as multiple aspects of neural dysfunction.