Mechanisms underlying telomere function in germ cell development

University Of Massachusetts Boston, Dorchester MA

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Abstract

Project Summary Infertility is a complex health issue that affects approximately 12% of couples and this rate increases with both maternal and paternal age. As many couples in developed countries prolong childbearing, the rate of couples seeking fertility treatments through assisted reproductive technology (ART) is likely to increase. Impaired fertility affects men and women equally and can be caused by a wide range of factors, including genetic and environmental factors that affect all aspects of the reproductive system. Thus, understanding mechanisms underlying reproductive health, especially with age, are important in diagnosing causes of impaired fertility and advising patients on potential success of ART. One predictor of reproductive health in men and women is telomere integrity, which is inversely associated with both gamete function and age. Therefore, understanding processes governing the functions of telomeres in gamete development will point to potential biomarkers and treatments to alleviate infertility. Telomere integrity is an important indicator of gamete quality and studies of animal models has demonstrated that telomere shortening in germ cells causes defects in gametogenesis and infertility. Telomeres are known to be important for dynamic chromosome movements that occur during meiosis to facilitate pairing of meiotic chromosomes. For example, telomerase deficient germ cells exhibit shortened telomeres, failed chromosome synapsis and aberrant chromosome segregation leading to defects in gamete development and function. However, it is unclear how telomere integrity regulates meiosis. This study aims to define the role of telomeres in meiosis and interrogate downstream processes that are affected by short telomeres in developing gametes. Zebrafish is an emerging model for studies in both telomere function in longevity and in investigating germ cell development. Our central hypothesis is that telomeres regulate chromosome dynamics during meiosis and that this regulation requires telomeres of sufficient length. Furthermore, we hypothesize that meiotic defects associated with shortened telomeres can be alleviated through modifying processes downstream of telomere length maintenance. The latter hypothesis is suggested by our discovery of a novel mutant that suppresses infertility and cellular senescence of telomerase deficient mutant zebrafish without rescuing telomere length. This suppressor mutation therefore restores gamete function in germ cells with short telomeres. To understand the precise role of telomeres in meiosis we will use quantitative methods to correlate telomere length with specific meiotic defects in mutants with shortened telomeres. Furthermore, we will characterize the meiotic events that are rescued by the suppressor mutation and define the molecular cause for this suppression. Understanding processes affected by loss of telomere integrity and mechanisms by which resulting defects can be rescued will lead to novel avenues to alleviate errors in gametogenesis, especially in individuals of increased age.