Chapter 6

Intracellular Ca2+ Signaling and Preimplantation Development D. Randall Armant

Abstract  The key, versatile role of intracellular Ca2+ signaling during egg activation after fertilization has been appreciated for several decades. More recently, evidence has accumulated supporting the concept that cytoplasmic Ca2+ is also a major signaling nexus during subsequent development of the fertilized ovum. This chapter will review the molecular reactions that regulate intracellular Ca2+ levels and cell function, the role of Ca2+ signaling during egg activation and specific examples of repetitive Ca2+ signaling found throughout pre- and peri-implantation development. Many of the upstream and downstream pathways utilized during egg activation are also critical for specific processes that take place during embryonic development. Much remains to be done to elucidate the full complexity of Ca2+ signaling mechanisms in preimplantation embryos to the level of detail accomplished for egg activation. However, an emerging concept is that because this second messenger can be modulated downstream of numerous receptors and is able to bind and activate multiple cytoplasmic signaling proteins, it can help the coordination of development through up- and downstream pathways that change with each embryonic stage. Keywords Intracellular calcium signaling · Egg activation · Preimplantation development · Blastocyst · Phosphoinositide-specific phospholipase C · Trophoblast · Inositol-1,4,5-trisphosphate · Platelet-activating factor · Lysophosphatidic acid · Integrins

D. R. Armant () Department of Obstetrics and Gynecology, Wayne State University C.S. Mott Center for Human Growth and Development, 275 E. Hancock Street, Detroit, MI 48201-1405, USA e-mail: [email protected] Anatomy and Cell Biology, Wayne State University, Detroit, MI, USA Program in Reproductive and Adult Endocrinology, NICHD, NIH, DHHS, 10 Center Drive, 20892-1103 Bethesda, MD, USA © Springer Science+Business Media New York 2015 H. J. Leese, D. R. Brison (eds.), Cell Signaling During Mammalian Early Embryo Development, Advances in Experimental Medicine and Biology 843, DOI 10.1007/978-1-4939-2480-6_6

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6.1 Cellular Regulation of Cytoplasmic Ca2+ Concentrations Ca2+ is a powerful second messenger required for cellular homeostasis that also regulates developmental processes (Berridge et al. 2003). Transient shifts in the concentration of cytoplasmic free Ca2+ direct several key events at the commencement of mammalian embryonic development. The partitioning and redistribution of Ca2+ among intracellular compartments contributes to a variety of mechanisms during fertilization and embryogenesis that control gene expression, mitochondrial activity, motility, secretion and protein trafficking, as detailed in a recent review (Miao and Williams 2012). Indicative of Ca2+ signaling within cells are changes in the concentration of cytoplasmic free Ca2+ (Tsien and Tsien 1990), which can be monitored in real time using a variety of Ca2+-sensitive intracellular probes (Tsien 1988). Intracellular Ca2+ stored within the endoplasmic reticulum (ER) is released into the cytosol to generate downstream signaling (Berridge et al. 2003). Additionally, extracellular Ca2+ can enter the cytoplasm by crossing the plasma membrane. In either case, a multitude of Ca2+ channels mediate Ca2+ entry into the cytosol, while it is transported back into the ER or out of the cell by Ca2+ exchangers and pumps, resulting in a transient increase in cytoplasmic free Ca2+. Ca2+ signals are ultimately generated both by the release of stored Ca2+ from the ER and the influx of extracellular Ca2+ across the plasma membrane. Ca2+ is released from the ER through two families of Ca2+ channels; inositol1,4,5-trisphosphate (IP3) receptors (ITPR1-3) and the ryanodine receptors (RYR1-3) (Berridge et al. 2003). The sarco(endo)plasmic reticulm Ca2+-ATPases (SERCA1-3) provide a pump to replenish Ca2+ in the ER. While the RYRs are activated by cytoplasmic Ca2+, itself, the ITPRs are activated by IP3, which is generated enzymatically along with diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (PIP2) by any one of 13 phosphoinositide-specific phospholipase C (PLC) isoforms. PLC activity can, in turn, be regulated through a wide array of upstream pathways that involve G-protein-coupled receptors (GPCR), small GTPases and tyrosine kinases, as well as free Ca2+. Ca2+ enters the cell through various plasma membrane channels to elevate cytosolic Ca2+ in response to upstream signals, as well as to sustain the capacity for Ca2+ signaling since plasma membrane Ca2+-ATPases (PMCAs) and the Na+/Ca2+ exchanger export it from the cell (Berridge et al. 2003). In excitable cells, voltage operated channels (VOCs) generate rapid Ca2+ influxes in response to membrane depolarization, and involve about 10 different channel proteins that comprise five VOC types (L, P/Q, N, R, T). Elevated cytoplasmic Ca2+ can, in turn, excite RYRs to trigger release from the ER as a mechanism of signal amplification. Additionally, there are Ca2+ channels operated by receptors (e.g., N-methyl-D-aspartate receptor, ATP receptor), second messengers (e.g., cAMP, arachidonic acid) and stretch, providing sensitivity to a diverse array of stimuli. Finally, the entry of extracellular Ca2+ is generally induced by the depletion of intracellular stores in a process referred to as capacitative or store-operated Ca2+ entry (SOCE) that ensures optimal refilling of the ER, and can extend cytosolic Ca2+ transients (Parekh and

6  Intracellular Ca2+ Signaling and Preimplantation Development

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Putney 2005). SOCE is activated by STIM1, a sensor of ER Ca2+ concentration that physically communicates with the plasma membrane protein ORAI1, which then forms a Ca2+-selective pore (Muik et al. 2012). There are a vast number of Ca2+-interacting proteins that become activated or inhibited as the Ca2+ concentration changes in the cytosol or in particular organelles. The generation of Ca2+ transients will therefore impact structural proteins, metabolism, signaling pathways and gene expression, which all play important roles in development. The sections which follow review some of the cellular events that Ca2+ signaling regulates during mammalian fertilization and preimplantation embryogenesis. It will become clear that Ca2+ signaling mechanisms arise not only during fertilization, but throughout development leading to blastocyst implantation, and that they regulate some of the key cellular events of the preimplantation phase (Fig. 6.1).

Fig. 6.1   Calcium signaling during fertilization and preimplantation development. Gametes and embryos are depicted at various stages of mammalian development to illustrate proposed roles for Ca2+ signaling. The process begins with gamete fusion and delivery of PLCζ by the sperm to initiate a series of Ca2+ transients responsible for the cortical reaction (exocytosis of the red vesicles shown), followed by extrusion of the second polar body and formation of two pronuclei. The approximate number of Ca2+ transients required for post-fertilization events are indicated to the right. Autocrine signaling and interactions with the reproductive tract during embryonic development extend the role of Ca2+ signaling. For example, PAF generates Ca2+ transients during the early cleavage stages that lead to CaMKII activation, which prevents apoptosis through downstream CREB activation. Speculation (?) suggests that the secretion of growth factors from the embryo and EGA could also be dependent on this signaling by Ca2+. Ca2+ signaling continues to regulate events leading to implantation. Examples are shown of proposed roles in cavitation and trafficking of integrins to the surface in response to LPA, CT, HBEGF and FN-induced integrin signaling as the blastocyst acquires competence for implantation. Details of these events are discussed in the article. Abbreviations: CaMKII, Ca2+/calmodulin kinase II; CT, calcitonin; CREB, cAMP responsive element binding protein; EGA, embryonic genome activation; FN, fibronectin; HBEGF, heparin-binding EGF-like growth factor; ITGA, integrin α subunit; LPA, lysophosphatidic acid; MAPK, mitogen activated protein kinase; PAF, platelet activating factor; PLC, phospholipase C

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6.2 Intracellular Ca2+ Signaling During Fertilization The role of intracellular Ca2+ signaling during fertilization, as illustrated at the top of Fig. 6.1, is well established and has been extensively reviewed elsewhere (Wakai and Fissore 2013; Ducibella and Fissore 2008). Fusion of sperm and egg triggers a series of cellular events known collectively as egg activation, which transitions the fertilized egg into embryogenesis. Activation of the metaphase II-arrested egg induces cortical granule exocytosis, molecular remodeling of the zona pellucida and plasma membrane, translational activation of stored maternal mRNA, resumption and completion of meiosis, extrusion of the second polar body, and pronuclear formation (Schultz and Kopf 1995). Sperm-egg fusion, or experimental injection of a sperm, rapidly initiates PLCdependent production of IP3 and activation of the ITPR to generate a large transient increase in the concentration of cytosolic free Ca2+, followed by a series of low frequency Ca2+ oscillations (Fig. 6.1) that last for several hours (Miyazaki et al. 1993; Cuthbertson et al. 1981). The production of these Ca2+ oscillations requires not only the initial burst of IP3, but also Ca2+ reuptake by the ER, Ca2+ influx across the plasma membrane, regulation of ER Ca2+ channels and Ca2+ buffering by other organelles (Wakai and Fissore 2013). The oocyte contains most isoforms of PLC, many which are capable of being activated by ligand-receptor interactions during fusion of the sperm and egg. However, IP3 production in the fertilized egg is initiated by PLCζ (Fig. 6.1), an isoform not expressed by the oocyte, but delivered by the entering spermatozoon (Swann and Lai 2013; Saunders et al. 2002). The decondensing sperm head releases PLCζ into the ooplasm where, unlike other PLC isoforms that utilize plasma membrane PIP2, it appears to hydrolyze PIP2 associated with small (

Intracellular Ca2+ signaling and preimplantation development.

The key, versatile role of intracellular Ca2+ signaling during egg activation after fertilization has been appreciated for several decades. More recen...
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