Fragile X Protein Regulates Cellular Proliferation and Oocyte Polarity by Controlling cb1 Levels During Drosophila Oogenesis

Abstract

Fragile X Protein (FMRP) is an RNA binding protein linked to the most common form of inherited mental retardation, Fragile X syndrome (FraX). Despite its ubiquitous expression and presence of non-neuronal phenotypes, FMRP function remains understudied outside of neural and synaptic development. In addition to severe cognitive deficits, FraX etiology also includes postpubescent macroorchidism, which is thought to occur due to overproliferation of the germline. Using a Drosophila model for FraX, I have shown that FMRP controls germline proliferation as well as dorso-ventral polarity during oogenesis. dFmr1 null ovaries exhibit egg chambers with increased numbers of germ cells and ventralized embryos. The number of cyclin E and phosphohistone H3 positive cells is increased in dFmr1 germaria compared to wild-type, suggesting that the mutant germline cells exhibit defects in proliferation. In addition, BrdU incorporation is increased during vitellogenesis, consistent with a prolonged S phase for endoreplicating nurse cells. Here I report the FMRP controls the levels of cbl mRNA in the ovary and that the overproliferation and polarity defects found in dFmr1 ovaries can be rescued by reducing cbl dosage in half. These data suggest a model whereby FMRP regulates cellular proliferation and polarity during oogenesis by controlling the E3 ubiquitin ligase cbl.