Greenblatt, Ethan

Research Interest

Biology relies on quickly adapting to environmental and developmental cues. Large cells such as oocytes and neurons can rapidly alter their proteomes by activating translation when needed. A number of reproductive and neuronal disorders are caused by misregulated translation. By understanding how disease factors control translation at the molecular level, we aim to open a path towards therapeutics for autism and ovarian disorders.

We have developed a model system for studying translational control in its “purest” state in vivo using mature Drosophila oocytes. Mature oocytes are giant cells which are transcriptionally inactive and rely entirely on the translation of stored mRNAs. We study how oocytes control the translation of their stored mRNAs by (1) characterizing translation genome-wide using ribosome profiling and RNA sequencing in wild type and mutant backgrounds (2) identifying novel factors using genetic screens and cell-type specific perturbations, and (3) discovering roles for translation factors in development and aging by studying effects on oogenesis and early embryonic development.

Projects

1. We found that Fmr1, a gene mutated in the most common autism and ovarian disorders, is part of a system that translates many of the largest proteins encoded in the genome (Greenblatt and Spradling 2018). We are interested in understanding how this system works, and whether restoring the normal balance between translational activators such as Fmr1 and translational repressors can ameliorate molecular defects underlying ovarian and autism spectrum disorders.
2. Oocytes contain large pools of mRNAs, which are preserved for several weeks. While mRNA levels are stable, translation declines substantially during aging (>50%), and this reduction is associated with meiotic failure and infertility (Greenblatt et al. 2019).During development human oocytes also cease transcription (~10 weeks prior to maturation). We will test the hypothesis that the inability to maintain sufficient translation from long-lived mRNAs leads to age-associated meiotic errors and follicle loss that limits human reproductive lifespan.
3. While the vast majority of genes are translationally repressed in oocytes, 6% of genes are translationally upregulated specifically during the oocyte’s prolonged developmental arrest (Greenblatt et al. 2019). Some of these genes – such as Fmr1, Hsp26 and Hsp27 act as “pilot lights,” prolonging oocyte function during extended periods of developmental arrest. We aim to understand the role of pilot light genes in oocytes preservation and whether these genes play important roles in other tissues such as the nervous system.

Current Lab Members

Kayla Judson: Research Technician

Xueling Kong: Undergraduate Researcher

Lucy Chi: Undergraduate Researcher