Mammalian sperm are not able to fertilize eggs immediately after ejaculation. They acquire fertilization capacity in the female tract in a process known as capacitation. Initially, capacitation was defined using fertilization as an end-point. However, a variety of evidence suggests that the functional changes occurring in the sperm during capacitation are not one event, but a combination of sequential and concomitant processes. These processes are associated with changes in the motility pattern (e.g. hyperactivation) and with preparation of sperm to undergo an agonist-stimulated acrosome reaction. At the molecular level, capacitation is associated with the activation of a cAMP signaling pathway, increase in intracellular pH, changes in the sperm plasma membrane potential, increase in tyrosine phosphorylation and with up-regulation of intracellular Ca2+ concentration ([Ca2+]i). In particular Ca2+ plays central roles in the regulation of both hyperactivation and the AR. However, the molecular mechanisms that control [Ca2+]i in sperm are not well established. The central hypothesis underlying this proposal posits that hyperactivation is the consequence of crosstalk between cAMP and Ca2+-depending signaling pathways. The objective of this proposal is to understand how Ca2+ and other signaling pathways (e.g. increase in pHi, cAMP and changes in Em) integrate during capacitation.

Public Health Relevance

Difficulties in earlier efforts to fertilize mammalian eggs in vitro were due mainly to a lack of comprehension of sperm physiology. This proposal is aimed to understand the molecular basis of sperm capacitation with emphasis in the regulation of the crosstalk between Ca2+ homeostasis and other signaling pathways in sperm. Accomplishment of these goals will provide tools for improving current Assisted Reproductive Technology (ART) methods and to identify novel contraceptive targets.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD038082-12A1
Application #
8697214
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Moss, Stuart B
Project Start
2000-07-01
Project End
2019-03-31
Budget Start
2014-06-02
Budget End
2015-03-31
Support Year
12
Fiscal Year
2014
Total Cost
$312,770
Indirect Cost
$100,660
Name
University of Massachusetts Amherst
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003
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Beltrán, Carmen; Treviño, Claudia L; Mata-Martínez, Esperanza et al. (2016) Role of Ion Channels in the Sperm Acrosome Reaction. Adv Anat Embryol Cell Biol 220:35-69
Navarrete, Felipe A; Alvau, Antonio; Lee, Hoi Chang et al. (2016) Transient exposure to calcium ionophore enables in vitro fertilization in sterile mouse models. Sci Rep 6:33589
Ramos-Espiritu, Lavoisier; Kleinboelting, Silke; Navarrete, Felipe A et al. (2016) Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase. Nat Chem Biol 12:838-44
Stival, Cintia; Puga Molina, Lis del C; Paudel, Bidur et al. (2016) Sperm Capacitation and Acrosome Reaction in Mammalian Sperm. Adv Anat Embryol Cell Biol 220:93-106
Alvau, Antonio; Battistone, Maria Agustina; Gervasi, Maria Gracia et al. (2016) The tyrosine kinase FER is responsible for the capacitation-associated increase in tyrosine phosphorylation in murine sperm. Development 143:2325-33
Navarrete, Felipe A; García-Vázquez, Francisco A; Alvau, Antonio et al. (2015) Biphasic role of calcium in mouse sperm capacitation signaling pathways. J Cell Physiol 230:1758-69
Wallingford, Mary C; Filkins, Rachel; Adams, Danielle et al. (2015) Identification of a novel isoform of the leukemia-associated MLLT1 (ENL/LTG19) protein. Gene Expr Patterns 17:11-5
Romarowski, Ana; Battistone, María A; La Spina, Florenza A et al. (2015) PKA-dependent phosphorylation of LIMK1 and Cofilin is essential for mouse sperm acrosomal exocytosis. Dev Biol 405:237-49
Escoffier, Jessica; Navarrete, Felipe; Haddad, Doug et al. (2015) Flow cytometry analysis reveals that only a subpopulation of mouse sperm undergoes hyperpolarization during capacitation. Biol Reprod 92:121

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