Ethan Greenblatt

Oocytes (egg cells) survive long periods of dormancy for up to several decades - women are born with all of the oocytes they will ever have. At the same time, infertility due to defects during egg development is a major societal problem: the rate of human miscarriage is estimated to be between 30% and 70%.

We take advantage the experimental accessibility of Drosophila (fruit fly) oocytes to understand the molecular basis for infertility. We have found that genes that are damaged in patients experiencing infertility also play important roles for fruit fly fertility. By performing experiments on fruit flies that would be challenging in other animals, we study the function of genes that are frequently mutated in human reproductive disorders, as well as neurological disorders like autism. These studies have led to surprising findings, such as finding a critical role for the autism spectrum disorder-associated gene Fmr1 to promote the production of giant proteins. We have also discovered a potential new source of damage during oocyte aging. We found that oocytes fail to maintain gene expression (translation) as they age, which may represent their "Achilles' heel." We aim to leverage our discoveries to come up with new therapeutic approaches for reproductive and neurological disorders.

We use the Drosophila oocyte as a model system for understanding how translation is controlled in vivo and how translation goes awry during aging and in disorders ranging from premature ovarian failure to autism. We combine a variety of molecular and genomic approaches (e.g. ribosome profiling, RNA sequencing, single molecule FISH, CRISPR gene-editing) with phenotypic screening to identify critical factors and discover their molecular functions.

Given the deep conservation between human and Drosophila biology, we believe that past and future discoveries will lead to fundamental insights into the basis for inherited ovarian and neurodevelopmental disorders and for the normal decline in function associated with aging.

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.