Meiosis is a fundamental process that is coupled to gamete development. Oocytes arrest in prophase of the first meiotic division to allow for growth. Release from prophase I occurs during meiotic maturation, but the molecular mechanisms regulating this process are incompletely understood. Meiotic maturation defects can result in infertility or in inaccurate segregation of chromosomes, leading to miscarriages and/or birth defects. The fruitfly Drosophila melanogaster offers sophisticated genetic and molecular tools, and a well described ovarian cell biology, making it a powerful system to investigate the control of meiotic maturation. Drosophila oocytes enter meiosis shortly after germline cyst formation and arrest in prophase I during most of their development. After meiotic maturation, oocytes arrest again in metaphase I until ovulation. In the prior funding period, we demonstrated that 1-Endosulfine (Endos) is required for meiotic maturation. Our data suggest that Endos promotes the stability of the cell cycle regulators CyclinA, Polo and Twine/Cdc25 (all known to be targets of the Anaphase Promoting Complex, or APC), and that it also has a separate role via inhibition of the E3 ubiquitin ligase Elgi to promote meiotic maturation. Expression of ENSA, the human 1- endosulfine, rescues the endos meiotic defect, and 1-endosulfine is expressed in mouse oocytes, suggesting conservation of the meiotic function of 1-endosulfine. Our overarching hypothesis is that Endos is a central regulator of meiotic maturation via two mechanisms: it inhibits the activity of the APC to allow the accumulation of key cell cycle regulators, and it antagonizes the ubiquitination of Elgi targets. We will test this hypothesis through the following specific aims: 1) to determine if Endos is a negative regulator of the APC;2) to determine how the E3 ubiquitin ligase Elgi regulates meiotic maturation downstream of Endos;and 3) to elucidate the molecular mechanism of action of Endos. Elucidation of the molecular mechanisms of meiotic maturation could potentially lead to therapies to address this cause of infertility, as well as to new contraceptives. Furthermore, this knowledge could also lead to technological strategies for in vitro maturation of human oocytes to complement current in vitro fertilization methodology.

Public Health Relevance

Failure of the oocyte to undergo meiotic maturation leads to infertility. Our prior work has identified Endos as a major regulator of meiotic maturation, and we propose to use powerful research tools in fruitflies to understand the function of this protein. Our studies could potentially lead to additional therapies to address infertility, as well as to technological strategies to complement current in vitro fertilization methodology.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Hamlet, Michelle R
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Johns Hopkins University
Schools of Public Health
United States
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Armstrong, Alissa R; Drummond-Barbosa, Daniela (2018) Insulin signaling acts in adult adipocytes via GSK-3? and independently of FOXO to control Drosophila female germline stem cell numbers. Dev Biol 440:31-39
Weaver, Lesley N; Drummond-Barbosa, Daniela (2018) Maintenance of Proper Germline Stem Cell Number Requires Adipocyte Collagen in Adult Drosophila Females. Genetics 209:1155-1166
Laws, Kaitlin M; Drummond-Barbosa, Daniela (2017) Control of Germline Stem Cell Lineages by Diet and Physiology. Results Probl Cell Differ 59:67-99
Hsu, Hwei-Jan; Drummond-Barbosa, Daniela (2017) A visual screen for diet-regulated proteins in the Drosophila ovary using GFP protein trap lines. Gene Expr Patterns 23-24:13-21
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Ables, Elizabeth T; Drummond-Barbosa, Daniela (2017) Steroid Hormones and the Physiological Regulation of Tissue-Resident Stem Cells: Lessons from the Drosophila Ovary. Curr Stem Cell Rep 3:9-18
Laws, Kaitlin M; Drummond-Barbosa, Daniela (2016) AMP-activated protein kinase has diet-dependent and -independent roles in Drosophila oogenesis. Dev Biol 420:90-99
Ables, Elizabeth T; Hwang, Grace H; Finger, Danielle S et al. (2016) A Genetic Mosaic Screen Reveals Ecdysone-Responsive Genes Regulating Drosophila Oogenesis. G3 (Bethesda) 6:2629-42
Weaver, Lesley N; Drummond-Barbosa, Daniela (2015) Gut healing: haemocytes aid via Sax and Tkv jazzes it down. Nat Cell Biol 17:707-9

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