Dietary components and environmental exposures can impact gamete function and fertility, but the underlying mechanisms are poorly understood. Prostaglandins are locally acting lipid hormones derived from essential dietary fats. In the human ovary, prostaglandins are thought to promote multiple processes critical for fertilization and may have a direct effect on sperm function. Their precise roles and regulatory mechanisms have been difficult to delineate, however. The nematode C. elegans is a powerful, yet simple model to investigate prostaglandins in reproduction. Results from the previous funding period have shown that C. elegans oocytes synthesize multiple structurally related F-series prostaglandins, including PGF1 and PGF2 stereoisomers. These prostaglandins function collectively and partially redundantly to guide sperm to the fertilization site, thereby increasing reproductive output. Strong preliminary evidence provided in this proposal supports the model that food-derived and other environmental cues perceived by ciliated sensory neurons are key regulators of ovarian prostaglandin synthesis. These external cues are known to modulate expression of a transforming growth factor beta (TGF-) homolog called DAF-7 in head ASI sensory neurons. The objective of this proposal is to delineate the mechanism by which female food-sensing neurons regulate sperm function. The central hypothesis is that ASI sensory neurons secrete DAF-7/TGF- to promote the synthesis of oocyte prostaglandins, which act via multiple G protein-coupled receptors (GPCRs) to stimulate sperm guidance.
Aim 1 proposes to delineate a mechanism by which female sensory neurons regulate sperm motility. The working hypothesis is that adult sensory neurons secrete DAF-7/TGF- to initiate a neuroendocrine signal transduction mechanism triggering prostaglandin synthesis in oocytes.
Aim 2 proposes to delineate the mechanism by which sperm transduce prostaglandin signals. The working hypothesis is that oocyte F-series prostaglandins act via multiple SRB class GPCRs upstream of Gq. These studies may reveal that food-derived cues are transmitted from sensory neurons in the female brain to the reproductive tract through conserved hormone networks that control sperm motility. Disrupting these female neuroendocrine mechanisms, either through genetic mutation, dietary changes, or environmental exposures, could impair sperm function. In addition, the results are likely to uncover new prostaglandin functions and regulatory mechanisms. Abnormal neuron to sperm signaling could contribute to infertility in humans and livestock.

Public Health Relevance

Nutritional deficiencies and environmental exposures can have a lasting, negative impact on gamete function and fertility. Prostaglandins are locally acting lipid hormones that are derived from dietary fats. This proposal aims to use the simple animal Caenorhabditis elegans to investigate fundamental mechanisms that couple nutritional status to gamete function via ovarian prostaglandins.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM085105-08
Application #
9014548
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Okita, Richard T
Project Start
2008-07-01
Project End
2018-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
8
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Pier, Bruce; Edmonds, Johnathan W; Wilson, Landon et al. (2018) Comprehensive profiling of prostaglandins in human ovarian follicular fluid using mass spectrometry. Prostaglandins Other Lipid Mediat 134:7-15
Hoang, Hieu D; Miller, Michael A (2017) Sperm Navigation Mechanisms in the Female Reproductive Tract. Results Probl Cell Differ 59:241-267
Cottee, Pauline A; Cole, Tim; Schultz, Jessica et al. (2017) The C. elegans VAPB homolog VPR-1 is a permissive signal for gonad development. Development 144:2187-2199
Hoang, Hieu D; Miller, Michael A (2017) Chemosensory and hyperoxia circuits in C. elegans males influence sperm navigational capacity. PLoS Biol 15:e2002047
Miller, Michael A (2015) Patterning with Diffusion Barriers. Dev Cell 35:395-6
Prasain, Jeevan K; Wilson, Landon; Hoang, Hieu D et al. (2015) Comparative Lipidomics of Caenorhabditis elegans Metabolic Disease Models by SWATH Non-Targeted Tandem Mass Spectrometry. Metabolites 5:677-96
McKnight, Katherine; Hoang, Hieu D; Prasain, Jeevan K et al. (2014) Neurosensory perception of environmental cues modulates sperm motility critical for fertilization. Science 344:754-7
Prasain, Jeevan K; Hoang, Hieu D; Edmonds, Johnathan W et al. (2013) Prostaglandin extraction and analysis in Caenorhabditis elegans. J Vis Exp :
Hoang, Hieu D; Prasain, Jeevan K; Dorand, Dixon et al. (2013) A heterogeneous mixture of F-series prostaglandins promotes sperm guidance in the Caenorhabditis elegans reproductive tract. PLoS Genet 9:e1003271
Miller, Michael A; Chin-Sang, Ian D (2012) Eph receptor signaling in C. elegans. WormBook :1-17

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