Abstract
The acrosome reaction (AR) is an exocytotic process essential for mammalian fertilization. It involves diverse physiological changes (biochemical, biophysical, and morphological) that culminate in the release of the acrosomal content to the extracellular medium as well as a reorganization of the plasma membrane (PM) that allows sperm to interact and fuse with the egg. In spite of many efforts, there are still important pending questions regarding the molecular mechanism regulating the AR. Particularly, the contribution of acrosomal alkalinization to AR triggering physiological conditions is not well understood. Also, the dependence of the proportion of sperm capable of undergoing AR on the physiological heterogeneity within a sperm population has not been studied. Here, we present a discrete mathematical model for the human sperm AR based on the physiological interactions among some of the main components of this complex exocytotic process. We show that this model can qualitatively reproduce diverse experimental results, and that it can be used to analyze how acrosomal pH (pHa) and cell heterogeneity regulate AR. Our results confirm that a pHa increase can on its own trigger AR in a subpopulation of sperm, and furthermore, it indicates that this is a necessary step to trigger acrosomal exocytosis through progesterone, a known natural inducer of AR. Most importantly, we show that the proportion of sperm undergoing AR is directly related to the detailed structure of the population physiological heterogeneity.
Highlights
The acrosome reaction (AR) is an exocytotic process in sperm that is essential for fertilization in many species, including mammals
The model hypothesizes that the free Ca2+ in the cytosol is inaccessible to the small space between the outer acrosomal membrane (OAM) and the plasma membrane (PM) at the final stages of the AR, and that the opening of local IP3 receptors (IP3R) provides the necessary Ca2+ that activates SYT and SNAP receptor family members (SNARE’s), allowing the fusion between membranes
We developed a discrete, synchronous, and deterministic regulatory network for the acrosome reaction in human sperm
Summary
The acrosome reaction (AR) is an exocytotic process in sperm that is essential for fertilization in many species, including mammals. We implement a generalization of the Gene Regulatory Network as formalized by Stuart Kauffman in 1969 (Kauffman, 1969) and used in many different systems (Mendoza and Alvarez-Buylla, 1998, 2000; Espinal et al, 2011; Yang et al, 2018) to construct a mathematical and computational model that represents the main physiological interactions involved in AR We show that this model can qualitatively reproduce many of the experimental results reported in literature and we use it to characterize how the physiological heterogeneity in a sperm population affects the proportion of cells capable of displaying spontaneous and Pg-induced AR. Our results indicate that physiological heterogeneity is closely related with the proportion of sperm capable of displaying AR, and that a pHa increase is an essential event in the process of the AR
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