The developmental program of the preimplantation embryo is readily modified by alterations in the microenvironment. The resultant change in trajectory of development can have long-acting effects that extend into post-natal life. Male and female embryos can respond differently to environmental modification during the preimplantation period. Recent data from our laboratory with bovine embryos indicate that sexual dimorphism in response to changes in the microenvironment could be mediated by gender-specific responses to maternal regulatory signals. Treatment of embryos with colony-stimulating factor 2 (CSF2) from Day 5-7 of development caused gender-specific alterations in characteristics of embryos after transfer to females and recovery at Day 15 of gestation. If this phenomenon of sexual dimorphism is a general one, gender-specific analysis will be required to understand basic mechanisms controlling development, environmental effects on embryonic development, and therapeutic approaches to improving fertility in women. The current proposal seeks to determine the extent to which regulation of embryonic development depends on gender. There are two immediate goals: to develop a model for understanding the molecular basis for how CSF2 exerts gender-specific effects on embryonic development and to evaluate whether the phenomenon of sexual dimorphism in regulation of preimplantation development is widespread (i.e., exists for more than one regulatory molecule). To meet these objectives, we will take advantage of a large amount of preliminary data from our laboratory that describes how CSF2 and two other uterine regulatory factors, insulin-like growth factor 1 (IGF1) and dickkopf-related protein 1 (DKK1), modify development of the bovine blastocyst. In particular, we will test whether actions of CSF2, IGF1 and DKK1 on embryos seen previously occur in a gender-specific manner when embryos are produced using X- or Y-sorted spermatozoa.
For Aim 1, gender differences in response of bovine morulae and blastocysts to CSF2 will be determined. Four experiments will be conducted to evaluate sexual dimorphism in regulation of the embryo by CSF2 with respect to gene expression in morulae and blastocysts, inhibition of apoptosis, and increase in numbers of cells in the inner cell mass of the blastocyst.
Aim 2 will determine whether sexual dimorphism exists for other regulatory factors by testing whether IGF1 and DKK1 exert actions on bovine embryos in a gender-specific manner. Experiments will be performed to determine differences between male and female embryos with respect to IGF1 actions on blastocyst development, gene expression and apoptosis and with respect to DKK1 actions on allocation of cells in the blastocyst to cells of the epiblast, primitive endoderm, and trophectoderm lineages. These experiments are important to develop research models for delineating mechanisms by which sexual dimorphism is established (Aim 1) and to determine the importance of sexual dimorphism as an important determinant of regulation of embryonic development (Aim 2).

Public Health Relevance

This project will test the hypothesis that gender-specific developmental programming represents sexual dimorphism in embryonic responses to maternally-derived regulatory factors. If the hypothesis is supported, it will have a large impact not only on our understanding of the fundamental processes controlling development, including the need to understand critical parts of development in a gender-specific context, but the research could lead to new therapeutic approaches for improving fertility and ART outcomes in women that involve gender-optimized procedures.

National Institute of Health (NIH)
Small Research Grants (R03)
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Developmental Biology Subcommittee (CHHD)
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Ravindranath, Neelakanta
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University of Florida
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