Gaps and barriers: Gap junctions as a channel of communication between the soma and the germline

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Review

Gaps and barriers: Gap junctions as a channel of communication between the soma and the germline Dana Landschaft Department of Neurobiology, Life Sciences Faculty, Tel Aviv University, Israel

A R T I C LE I N FO

A B S T R A C T

Keywords: Soma Germline Gap Junction channels Oocytes Weismann barrier

Gap junctions, expressed in most tissues of the body, allow for the cytoplasmic coupling of adjacent cells and promote tissue cooperation. Gap junctions connect also the soma and the germline in many animals, and transmit somatic signals that are crucial for germline maturation and integrity. In this review, we examine the involvement of gap junctions in the relay of information between the soma and the germline, and ask whether such communication could have consequences for the progeny. While the influence of parental experiences on descendants is of great interest, the possibility that gap junctions participate in the transmission of information across generations is largely unexplored.

1. Introduction

1.2. Gap junctions connect the somatic gonad and the germline

1.1. Segregation of the germline from the soma

In all metazoans gap junctions function to facilitate direct communication between cells [8]. Gap junctions are expressed abundantly in various tissues where they perform many different tasks [9]; for example, gap junctions form electrical synapses [10], contribute to pattern formation establishment [11–14], wound healing [15,16], regeneration [13,14,17–19] and embryonic development [20–22]. More than two dozen human diseases were linked to mutations in gap junction genes [23]. As many reviews are dedicated to gap junction function, structure, and regulation [8,9,24], we will only overview these topics briefly in this manuscript. Gap junctions allow for direct electrical and metabolic coupling between adjacent cells. Small metabolites, inorganic ions, and small secondary messengers are transferred via gap junctions [25,26]. Two gene families - Connexin (Cx) in vertebrates and Innexins (Inx) in invertebrates, have evolved to provide these functions. Interestingly, although there is no protein sequence similarity between the two gap junction types, the structural and functional homology is significant [27–29]. Gap junctions are regulated at multiple levels [26,30] and display varied voltage-dependent conductance modes that can be regulated by factors such as pH, transjunctional voltage, and phosphorylation [25,31,32]. Recently, in worms, it has been shown that going through a stress-resistant alternative developmental stage (dauer), leads to dramatic remodeling of the gap junction network across the nematode’s body [33]. Gap junctions play an important role in animal gonads, and allow communication between the germline and the somatic cells of the gonad; this communication is important for proper gametogenesis and disruptions of this crosstalk can result in infertility [34]. Across phyla, gametes and the somatic cells that surround them possess direct

The German evolutionary biologist, August Weismann, postulated the germ plasm theory in the late 19th century. Weismann determined that germ cells are separated from somatic cells, and that the germline alone participates in the inheritance process, transmitting the hereditary information from parent to offspring. Thus, Weismann rejected the involvement of somatic cells in heredity, and claimed that information flows in one direction only, from the germline to the soma [1–3]. If this dogma, which is also known as the “Weismann Barrier”, or “The Second Law of Biology” indeed holds, traits acquired by somatic cells cannot be inherited. While Weismann’s law was crucial for the formulation of the theory of evolution and for developmental biology, there are many “holes“ in the barrier. Multiple studies have demonstrated that under certain circumstances somatic information can be transferred to the germline in various organisms. Most notably, in the nematode Caenorhabditis elegans, a dedicated pathway has evolved to shuttle small RNAs from somatic cells to germ cells, and in the germline these adopted small RNAs induce multigenerational gene regulatory changes [4–7]. In this review we speculate on the importance of the signals that gap junctions transmit from the soma to the germline, and examine the possibility that some of the transmitted information can be maintained in the germline so that the development of the next generation would be affected. This possibility is largely unexplored, and therefore the aim of this review is to encourage future experimental studies.

https://doi.org/10.1016/j.semcdb.2019.09.002 Received 4 May 2019; Received in revised form 29 August 2019; Accepted 4 September 2019 1084-9521/ © 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: Dana Landschaft, Seminars in Cell and Developmental Biology, https://doi.org/10.1016/j.semcdb.2019.09.002

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For example, choline which provides one carbon unit for the biosynthesis of S-adenosylmethionine (SAM), the central methyl donor in the cell, is transferred to the oocyte from the somatic gonad through gap junctions [40,41]. One of the most studied models for nutritional and environmental effects on the epigenome is the Agouti mouse model. The mouse agouti viable yellow (Avy) allele contains an insertion of a retrotransposon upstream of the agouti gene, driving continuous expression of the agouti gene that results in yellow coat coloration and a variety of metabolic phenotypes (such as adult-onset obesity). CpG methylation on the Avy allele correlates inversely with Agouti expression. In isogenic population of Avy mice there is a wide variation of phenotypes ranging from yellow and obese (unmethylated) to pseudoagouti (brown-ish) and lean (methylated). The variation in phenotypes is partially heritable - progeny of agouti mothers are disproportionately agouti while progeny of pseudoagouti mothers skewed to brown, even though the population is isogenic [75,93]. Alterations in methyl donor availability, and specifically of choline, have been reported to affect the heritability of the agouti phenotype in the offspring [94]. Acetylation in the germline genome might also be affected by germline gap junctions with somatic cells. Acetylation is an important mark of epigenetic reprogramming and a dominant histone modification in the oocyte, suggested to affect chromosome dynamics [95,96]. Acetyl-coA is the primary acetyl donor for protein acetylation [97]. Acetyl-coA is created when pyruvate, the main product of glycolysis, is oxidized in the entry to the citric acid cycle as Acetyl-coA [98]. Since oocytes are unable to catabolize glucose as an energy source by themselves, these cells are dependent on supply from the somatic gonad. Mammalian granulosa cells metabolize glucose to pyruvate, and it was suggested that this metabolite is then transmitted to the oocyte via gap junctions [99–101]. Thus, the supply of two substrates which are important for methylation and acetylation, choline and pyruvate, depends on the deposition of metabolites from the somatic gonad to the oocyte through gap junctions. Therefore, there appears to be a link between gap junction mediated metabolic coupling and DNA/chromatin modifications, which could subsequently affect gene expression in the progeny.

cytoplasmic connections mediated by gap junction channels [35–37]. In the mammalian ovary, gap junctions are localized between the oocyte and the somatic cells of the follicle [38–42]. Deletion of follicular gap junctions results in halting of oocyte development [43–45]. In amphibia, microscopic examination of the ovarian follicle revealed numerous contact points between follicle cells and the oocyte [46], later identified as gap junctions [35,47]. In insects as well, somagermline connections via gap junction channels are abundant [48–54]. For example, in Drosophila melanogaster, the protein zero population growth (Zpg) encoding the gap junction protein Innexin 4 (inx-4) is expressed solely in nurse cells and oocytes at high levels throughout oogenesis [52,55]. The gene inx-4 is required for early germ cells initiation, differentiation, survival and for proper embryogenesis [52,54,56]. In C. elegans, each gonadal arm possesses five pairs of somatic sheath cells, which form a single layer covering the germline [57]. Gap junction channels between the soma and the developing germline are evident along the nematode’s gonad [57,58]. Sheath cells at the distal tip are linked by gap junctions to the underlying germ cells, and are required for germline proliferation, meiotic differentiation and early embryonic development [59]. Proximal sheath cells are connected by gap junctions to the proximal oocyte, closest to the spermatheca. These gap junctions function to regulate oocyte meiotic maturation in preparation for the fertilization process [60–62]. In males, many aspects of sperm development are regulated by the somatic cells of the testis [63,64]. Gap junctions between spermatogonia and the soma are evident across phyla, from mammals [65–68] to insects [37,69]. In the mammalian spermatheca, loss of the gap junction protein Cx43 results in halt of spermatogenesis and when Cx43 expression decreases, sperm motility is harmed [64,70,71]. T esticular Cx43, was shown to participate in the relay of environmental stress, such as heat shock and toxin exposure [72–74]. Other connexins located in the mammalian testis were shown to function in the bloodtestis barrier, and in germ cell apoptosis [64]. 2. Gap junctions affect epigenetic pathways acting in the germline We speculate that gap junctions which connect the soma and the germline could participate in the transmission of parental responses to the progeny. Somatic responses to changes in the environment have been suggested to change the progeny via various mechanisms, for example by affecting the DNA methylation and histone modifications in the germline [75,76]. Another example being the transfer of somatic small RNAs (specifically exogenously double strand-derived small RNAs) to the germline in nematodes and small RNAs transfer from the somatic epididymis tissue to the sperm in mammals [7,77]. In many organisms, small RNAs induce chromatin modifications which, in turn, affect small RNA biogenesis [78–80]. We will now examine the role gap junctions could be playing in transferring information from the somatic gonad to the germline. Specifically, we will discuss how gap junctions may influence the specific processes of histone and DNA modifications and RNA transfer from the soma to the oocyte.

2.2. Regulation of meiotic arrest by gap junctions In most animals, the oocyte arrest in meiotic prophase I, enabling the oocyte to assemble the various components that will allow it to gain meiotic and developmental competence [102]. The coupling by gap junctions of follicle cells and the oocyte is required for meiotic arrest, as it governs the bi-directional flow of intracellular signals between the two cell types [40,41,45,103,104]. Cyclic adenosine monophosphate (cAMP) generated in arrested oocytes maintains PKA activity, which inhibits maturation-promoting factor (MPF), and maintains meiotic arrest. Cyclic guanosine monophosphate (cGMP) transfer to the oocyte, from somatic cumulus cells, was shown to inhibit the degradation of cAMP by PDE3A phosphodiesterase and thus to govern the maintenance of meiotic arrest in the oocyte [105–108]. Upon hormonal stimulation, cGMP levels decrease in the somatic gonad and diffuse out of the oocyte, again, through gap junctions. This results in the activation of MPF and the resumption of meiotic maturation [39,42,109]. In the germline, the coordination of DNA directed events must be tightly regulated both spatially and temporally. During oocyte meiotic arrest in prophase I, meiotic recombination takes place and the chromatin of the oocyte goes through distinct morphological changes [110]. Gap junction channels were shown to be important for proper chromatin remodeling during oocyte maturation by cAMP related pathways [96,111,112]. Interrupting oocytic gap junction function with a chemical agent caused a rapid chromatin condensation. The effect was cancelled with the inhibition of protein de-esterase PDE-3, responsible for the degradation of cAMP [113]. In both C. elegans and mice, the levels of histone methylation undergo global changes at the early stages

2.1. Possible consequences of metabolic coupling of the soma and the germline by gap junctions Drastic changes in dietary intake affect the immediate progeny in many organisms [81–85] and in some cases the effect was described to proceed beyond that to F2 and even F3 generation [6,86–89]. Protein and DNA modifications, such as methylation and acetylation are strongly affected by the metabolic state of the cell, as these processes depend on the supply of chemical group donors [76]. Gap junctions mediate the metabolic cooperativity between oocytes and their companion somatic cells [34,44,90]. Indeed, many metabolites are transferred from the somatic gonad to the oocyte via gap junctions [40,41,90–92]. 2

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germline is tightly associated with the somatic gonad that encapsulate it. This association is important for key processes of germline development and maturation, ovulation and fertilization. When considering the question of how somatic information is conducted to the germline to affect the next generations (to defy the “Weismann Barrier”) it is interesting to examine the physical connections of germ cells and the neighboring tissue with which they interact directly. The communication between the germline and the somatic cells of the gonad appears to be important for regulation of epigenetic processes known to be critical in transgenerational inheritance of gene regulatory responses. Perturbing gap junction function could hinder the deposition and maintenance of different epigenetic marks, and also small RNA inheritance. Here, we briefly examined several uses of gap junctions as mediators between the soma and the germline, and examined whether these functions could transmit information transgenerationally. Specifically, metabolic coupling could allow delivery of somatic metabolites to the germline, and thus affect pools of substrates that are necessary for germline DNA and histone modifications. In addition, gap junctions could be important for controlling meiotic arrest and oocyte maturation, two processes which are crucial for fertilization, and that may affect gene regulation in the embryo. Lastly, transfer of yolk proteins to the oocyte, a process known to be regulated by gap junctions, might affect transfer of RNA from the soma to the germline, as in both nematodes and flies, RNA transfer was linked to yolk uptake by oocytes. The inheritance of non-DNA sequenced-based epigenetic information is dependent upon its successful transfer to the germline. While the identity and function of the information units that proceed to the germline are the focus of many research projects, the path by which these factors travel is still vague. In this review we suggest that gap junction are bridges that connect the soma and the germline.

of meiotic prophase I during chromosome pairing. H3K9me levels in C. elegans were reported to undergo global changes during this time frame [114]. In C. elegans, H3K9 methylation was found to affect biogenesis of small RNAs, and RNA interference (RNAi) inheritance [78,115]. Genomic imprinting is one well studied feature of the germline epigenome. Under this phenomena, DNA methylation is put to use in order to control the expression of genes and growth factors in a parent of origin dependent manner [75]. In the germline, epigenetic reprogramming of imprinted genes is critical and disruption of the germline imprints can result in the development of imprinting disorders such as Silver–Russell Syndrome (SRS). Oocytes from mice mutated in connexin 37 (Cx37), fail to grow in size and fail to gain methylation at a specific loci relevant in SRS [116]. Thus, gap junction may not only support the supply of methylation building blocks but could also be involved in its tight temporal regulation. 2.3. Potential role of gap junction regulated yolk transfer in soma-germline RNA transfer Yolk uptake is a key step of oocyte maturation in many egg-laying species. Yolk proteins, vitellogenins, provide essential building blocks to support the rapid embryonic development. Vitellogenins, produced primarily in fat bodies, are secreted into the circulatory system and are transported into the oocyte by receptor-mediated endocytosis [117,118]. Examples from frogs and insects show that vitellogenin uptake is regulated by the somatic cells of the gonad through gap junctions by calmodulin and cAMP signaling. Uncoupling or down regulating gap junctions in oocytes disables vitellogenin endocytosis [53,119–124]. Gap junctions are modulated by the bioelectrical state of cells. Gap junctions are oftentimes voltage-gated and facilitate not only molecular coupling between cells, but also electrical coupling [28,125,126]. This characteristic is intriguing, because, at least in theory, the signals transferred by gap junctions to the oocyte will depend in part on the bioelectrical state of the parents’ soma. In insects, the process of yolk uptake coincides with bioelectrical phenomena. In Drosophila melanogaster follicle, during the oocyte vitellogenic stage, the extracellular electrical pattern shifts around the follicle, and only during this stage oocytes show an inward current located at the posterior pole of the follicle [127]. Similar phenomena were also described in moths and cockroaches [49,128]. In C. elegans, uptake of vitellogenin is probably linked to the transfer of RNA from the soma to the oocyte, and consequently also to multigenerational gene regulation. Intergenerational silencing of somatic genes through the RNAi machinery depends on the transmission of dsRNA to the mature oocyte. dsRNA molecules that were labelled with a fluorescent marker were documented as they move from the extracellular space and into the oocyte, in conjugation with yolk particles and presumably within vesicles. Furthermore, the same transporter protein, RME-2, is required for endocytosis of dsRNAs and yolk from the soma to the germline [7,129]. In Drosophila, the retrotransposon ZAM of the gypsy family is transferred to the oocyte from the soma by the same pathway involved in vitellogenin uptake; ZAM particles fail to gain access to the oocyte when gap junctions are inhibited [124,130]. Thus, the translocation from the soma to the oocyte of dsRNA in nematodes, and transposon RNA in fruit flies, seems to depend upon the oocyte’s vitellogenic stage both temporally and mechanistically. Many studies have shown that gap junctions traffic messages by which the somatic cells of the gonad regulate endocytic yolk uptake, a process accompanied by distinct bioelectrical changes in insects. Thus, it is possible that via gap junctions, electrical phenomena could affect interand trans-generational inheritance of RNA.

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3. Summary Across the animal kingdom, from nematodes to mammals, the 3

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