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Of Mice and Worms: Novel Insights Into ClC-2 Anion Channel Physiology

Kevin Strange

Anesthesiology Research Division, Laboratories of Cellular and Molecular Physiology, Departments of Anesthesiology, Molecular Physiology and Biophysics, and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232

	Abstract

 
ClC anion channels are found in all major groups of organisms. Recent studies in nematodes and mice suggest that the function and regulation of ClC-2 have been conserved over vast evolutionary time spans. These studies illustrate the experimental advantages of using genomically defined nonmammalian model organisms for characterizing ClC channel functional genomics.

	Introduction

Top Introduction ClC anion channels: a... ClC biology in C.... Regulation and physiological... Of mice and worms Conclusions References

 
Worldwide efforts to sequence the genomes of various organisms began in earnest in the late 1980s. These sequencing efforts have been stunningly successful. To date, numerous microbial genomes as well as genomes of the yeast Saccharomyces, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, the flowering plant Arabidopsis thaliana, and human have been fully sequenced. Genome sequences for many other organisms will soon follow.

Genetics underlies all areas of biological inquiry, and the availability of genome sequences of evolutionarily diverse organisms has revolutionized biomedical research. Genome sequencing forms the foundation of the field of "functional genomics," which aims to assign function to all of the genes in an organism's genome and to elucidate the organization, integration, and control of networks of proteins that work in concert to give rise to specific biological traits.

Mammalian physiologists attempting to unravel the genetic bases of complex physiological processes now have a host of powerful tools at their disposal. One of those tools is nonmammalian "model organisms." What is a model organism? Physiologists have a long tradition of using nonmammalian animals to address mammalian physiological problems. For example, our initial understanding of action potential generation came from the squid giant axon. Renal physiologists have studied amphibian epithelia for decades to gain insights into distal nephron function, and the electric organ of the Torpedo ray provided the first insights into ClC anion channel biology. The physiologist and Nobel laureate August Krogh emphasized the importance of studying physiology in nonmammalian organisms. He believed that there is an animal in which almost every biological problem can be studied most readily, a belief that is often referred to as "Krogh's Principle."

Krogh would define a model organism as any organism that provides some experimental advantage for the study of a physiological process. The term "model organism," however, has taken on a more explicit meaning in the postgenome world. Model organisms are "simpler," genomically defined organisms that are easy to grow in the laboratory, produce large numbers of offspring, and have relatively short life cycles, making them suitable for detailed genetic analyses. These characteristics allow more rapid, efficient, and economical manipulation, and hence understanding, of gene function than what is possible in "complex" organisms.

Despite the narrowing of the definition of "model organism," Krogh's Principle applies, perhaps more than ever, in the postgenome field of functional genomics. If one wishes to define the genetic basis of a complex physiological process, studying it in a model system that is less complicated than a mammal, that is genetically tractable, and in which it is relatively easy to manipulate gene expression makes sound experimental sense. Organisms such as Saccharomyces, C. elegans, Drosophila, and even the plant Arabidopsis are powerful experimental systems for addressing physiological problems common to all eukaryotes. Recent studies of ClC anion channel function in C. elegans illustrate this point (17).

	ClC anion channels: a brief overview

Top Introduction ClC anion channels: a... ClC biology in C.... Regulation and physiological... Of mice and worms Conclusions References

 
Members of the ClC superfamily of voltage-gated Cl^- channels have been identified in plants, yeast, eubacteria, archaebacteria, and various invertebrate and vertebrate animals (19). Although the function and regulation of most ClC channels are obscure, the conservation of ClC genes in widely divergent organisms suggests that they play important and fundamental physiological roles.

Nine ClC genes have been described in mammals. These genes comprise three distinct subfamilies: ClC-1, -2, -Ka/K1, and -Kb/K2; ClC-3, -4, and -5; and ClC-6 and -7. Knockout studies and the identification of disease-causing mutations indicate that ClC channels function in the regulation of membrane potential, Cl^- transport in intracellular vesicles, and epithelial Cl^- transport (19).

	ClC biology in C. elegans

Top Introduction ClC anion channels: a... ClC biology in C.... Regulation and physiological... Of mice and worms Conclusions References

 
C. elegans was introduced as a model system for genetic research in the 1960s by the molecular biologist Sydney Brenner. Brenner recognized that C. elegans provided numerous experimental advantages for defining the genetic basis of development and other biological processes. The animal has a short life cycle, produces large numbers of offspring by sexual reproduction, and can be cultured easily in the laboratory. Sexual reproduction occurs by self-fertilization in hermaphrodite worms or by mating with males. The ability to readily self-fertilize or cross nematodes is of great utility for genetic analyses of complex processes. Finally, C. elegans is a highly differentiated animal but is comprised of <1,000 somatic cells. C. elegans thus has substantial cellular complexity but is not too complex and provides a tractable system for elucidating fundamental aspects of cell biology and physiology.

C. elegans was the first multicellular organism to have its genome fully sequenced. Analysis of the genome revealed the presence of six ClC genes. These genes have been termed Cl^- channel homologues: clh-1 through -6 (14,16) or CeClC-1 through -6 (18). I will use the clh nomenclature to avoid confusing worm channels with their mammalian counterparts.

Nematodes have a full complement of "mammalian-type" ClC channels. The six CLH channels are representative of the three mammalian ClC channel subfamilies (19). Green fluorescent protein (14,18) and lacZ (16) reporter studies have demonstrated that clh genes are expressed in a variety of worm cell types including neurons, muscle cells, and epithelial cells. Very little is known about the functional biology of these channels. However, deletion of clh-1 has been shown to increase body width. This and other observations suggest that the channel might play a role in whole animal osmoregulation (16).

	Regulation and physiological role of a C. elegans ClC-2 ortholog

Top Introduction ClC anion channels: a... ClC biology in C.... Regulation and physiological... Of mice and worms Conclusions References

 
It is safe to say that C. elegans violates Krogh's Principle when it comes to electrophysiology. Most somatic cells in C. elegans are quite small, and a tough, pressurized cuticle surrounding the animal limits access for study by patch clamp methods. Nevertheless, there are cell types that can be accessed relatively easily for patch clamp studies, and they provide excellent models for the study of ion channel function and regulation.

One of those cell types is the animal's oocytes. Figure 1 shows a schematic diagram and differential interference contrast micrograph of the C. elegans hermaphrodite gonad. The gonad consists of two U-shaped arms connected to a common uterus. Oocytes develop in the proximal region of the gonad and accumulate in a single row of graded developmental stages. The most differentiated oocyte is positioned next to the spermatheca, where it undergoes meiotic maturation and is then ovulated into the spermatheca and fertilized. Earlier stage oocytes mature and are ovulated in a sequential, assembly line-like fashion (11,13).

View larger version (46K): [in this window] [in a new window]   FIGURE 1. Schematic diagram and differential interference contrast micrograph of the adult hermaphrodite gonad. Oo, oocyte; Spt, spermatheca; Emb, embryo. Scale bar in micrograph is 20 µm. Figure reprinted from Rutledge et al. (17) with permission from Elsevier Science.

View larger version (17K): [in this window] [in a new window]   FIGURE 2. Functional and molecular identification of anion channel activity in C. elegans oocytes. A: basal and swelling-activated whole cell currents elicited by stepping oocyte membrane voltage from –100 mV to +80 mV in 20-mV steps from a holding potential of 0 mV. B: disruption of whole cell anion current by RNAi. Swelling-induced current activation is inhibited ~95% in oocytes isolated from worm gonads microinjected with clh-3 double-stranded (ds) RNA. Microinjection of worm gonads with clh-1, -2, -4, -5, or -6 dsRNA had no significant effect (P > 0.05) on swelling-induced current activation. Figure reprinted from Rutledge et al. (17) with permission from Elsevier Science.

dsRNA readily crosses cell membranes by unknown mechanisms. Thus it can be administered to worms systemically by feeding it to the animal or by microinjection anywhere into the animal's body. We made dsRNAs to each of the six clh genes, microinjected them individually into the gonads of worms, and then dissected out and patch clamped oocytes 20–24 h later. As shown in Fig. 2B, dsRNA complementary to clh-1, -2, -4, -5, or -6 had no effect on swelling-induced current activation in oocytes. However, clh-3 dsRNA almost completely abolished the current. These observations, along with single oocyte RT-PCR measurements (17) and heterologous expression studies (Böhmer, Nehrke, and Strange, unpublished observations), demonstrated that clh-3 encodes the channel responsible for the oocyte current.

What is the physiological role of CLH-3? ClC-2 is widely expressed in mammalian cells and tissues and has been proposed to function in transepithelial salt and water transport, intracellular Cl^- homeostasis, and cell volume regulation (19). Disruption of CLH-3 expression by RNA_i had no obvious effect on the physiology of oocytes, including their ability to volume regulate (17).

Further experimental analysis revealed an intriguing pattern of CLH-3 activity in the nematode oocyte. Oocytes must undergo DNA reduction divisions or meiosis before fertilization. Like oocytes of most animals, C. elegans oocytes are arrested in prophase I of meiosis I during much of their development. Just before fertilization, meiosis is reinitiated, a process referred to as meiotic maturation. In nonmaturing oocytes, CLH-3 is quiescent and can be activated by swelling. However, in oocytes undergoing meiotic maturation, CLH-3 is constitutively active. This suggested that the channel might play a role in meiotic cell cycle progression, fertilization, and/or early development. Disruption of channel expression by RNA_i, however, has no effect on these reproductive events (17).

Oocytes are surrounded by smooth muscle-like myoepithelial sheath cells (Figs. 1 and 4). Before meiotic maturation, sheath cells contract weakly and intermittently at a basal rate of 7–8 contractions/min. Sheath cell ovulatory contractions are triggered ~4–5 min after the start of meiotic maturation. During this contractile cycle, both the force and rate of sheath contractions increase dramatically. At the peak of contractile activity, the spermatheca dilates and the oocyte is ovulated and fertilized. This oocyte maturation and ovulation cycle is repeated every 20–40 min (13). Both sheath cell ovulatory contractions and spermatheca dilation are controlled by signals from the maturing oocyte (13). However, the precise mechanisms of intercellular signaling are incompletely understood.

View larger version (29K): [in this window] [in a new window]   FIGURE 4. Cartoon illustrating the close cell-to-cell interactions observed in the C. elegans gonad, mouse seminiferous tubule, and mouse retina. RPE, retinal pigment epithelium.

Reporter studies have failed to detect CLH-3 expression in sheath cells (14,18). We therefore postulated that activation of CLH-3 in the maturing oocyte modulates sheath cell contractions. How would this occur? Oocytes are coupled to sheath cells by gap junctions (11), indicating that the two cell types likely communicate by chemical and electrical signals. The simplest experimentally testable model that we can envision is shown in Fig. 3. We proposed that activation of CLH-3 depolarizes the oocyte and electrically coupled sheath cell membranes. Depolarization in turn inhibits Ca²⁺ influx into the sheath cell via store-operated Ca²⁺ channels that are triggered by depletion of inositol 1,4,5-trisphosphate-regulated intracellular Ca²⁺ stores. As maturation progresses, inhibition of CLH-3 activity, activation of cation channels, or disruption of oocyte-sheath cell gap junction communication could repolarize sheath cells and initiate Ca²⁺ influx and contraction.

View larger version (21K): [in this window] [in a new window]   FIGURE 3. Postulated mechanism by which CLH-3 modulates sheath cell contractile activity. A factor secreted by the maturing oocyte is thought to trigger ovulatory contractions of gonadal sheath cells (13). CLH-3 is activated at the beginning of meiotic maturation. Channel activation depolarizes the oocyte and electrically coupled sheath cell plasma membranes. Depolarization in turn inhibits Ca2+ influx through plasma membrane Ca2+ channels [store-operated channel (SOC) activated by depletion of intracellular Ca2+ stores. During the late stages of meiotic maturation when the oocyte is ready to be ovulated and fertilized, sheath cell membrane potential is hyperpolarized, allowing Ca2+ influx and initiation of ovulatory contractions. Hyperpolarization may occur by inactivation of CLH-3, activation of cation channels, and/or uncoupling of sheath cell/oocyte gap junctions.

	Of mice and worms

Top Introduction ClC anion channels: a... ClC biology in C.... Regulation and physiological... Of mice and worms Conclusions References

 
Jentsch and co-workers (3) recently succeeded in knocking out the ClC-2 gene in mice. None of the previously proposed functions of ClC-2 (19) were disrupted in the knockouts, but the mice exhibited severe degeneration of the testes and retina. Although the precise functions of ClC-2 were not revealed by these studies, the authors suggested that the channel plays a role in regulating localized extracellular ionic environments in these two tissues (3). Based on our studies of CLH-3 in C. elegans (17), it is interesting to speculate on other possible roles of ClC-2 that are consistent with the mouse knockout results.

The seminiferous tubule epithelium is composed of Sertoli cells and germ cells (Fig. 4). Spermatogonia are located on the basal side of the Sertoli cells and undergo mitosis to form primary spermatocytes. Developing germ cells migrate through the spaces between Sertoli cells toward the luminal surface of the seminiferous tubule. Primary spermatocytes undergo the first meiotic cell division, forming secondary spermatocytes. The secondary spermatocytes progress through meiosis II, giving rise to spermatids that then differentiate into spermatozoa. In ClC-2 knockout mice, the testicles degenerate shortly after birth. Seminiferous tubules have reduced diameters and closed lumens. Germ cell development is severely disrupted in young males. Males older than 6 mo lack germ cells (3).

What do the C. elegans hermaphrodite gonad and mammalian testis have in common? Fig. 4 is a cartoon illustrating the two tissues. The worm gonad and mammalian testis are tissues involved in reproduction, and both contain cell types, oocytes and spermatogonia, that depend critically on precise timing and functioning of the meiotic cell cycle. In addition, the gonad and testes are comprised of cells that interact closely and communicate with one another.

As noted earlier, C. elegans oocytes are surrounded by and directly coupled to gonadal sheath cells via gap junctions (11) (Figs. 1 and 4). Signaling between sheath cells and oocytes is essential for regulating ovulation and meiotic maturation (13). Sheath cells also contain specialized pores through which intestinally synthesized yolk proteins are transported to the oocytes (11).

Sertoli cells control development of germ cells into spermatozoa by direct, cell-to-cell physical interaction, by secretion of growth factors and nutrients, and by controlling the ionic environment within the seminiferous tubule lumen. The Sertoli cells also phagocytose degenerate germ cells and residual cytoplasm produced during sperm maturation (9,10). ClC-2 is expressed on the basal side of Sertoli cells in patches of membrane-contacting germ cells (3).

It is conceivable that ClC-2 may have signaling functions in the testes that are analogous to the signaling role proposed for CLH-3 in the nematode gonad (17) (Fig. 3). Interestingly, spermatogonia and Sertoli cells are coupled by gap junctions (4). ClC-2 could thus participate in intercellular signaling pathways that control germ cell development. ClC-2 could also play a signaling role that regulates Sertoli cell function. The phagocytic activity of Sertoli cells is essential for normal germ cell development (9). Calcium signaling events play essential roles in controlling phagocytosis in many cell types (7). In neutrophil granulocytes, the membrane potential depolarizes dramatically during phagocytosis due to electrogenic superoxide production (7,8). Geiszt et al. (8) have shown that neutrophil membrane potential has significant impact on intracellular Ca²⁺ dynamics. Membrane depolarization inhibits refilling of intracellular Ca²⁺ stores by inhibiting Ca²⁺ influx through store-operated Ca²⁺ channels. Perhaps ClC-2 modulates Ca²⁺ signaling events in Sertoli cells by modulating plasma membrane potential.

The vertebrate retina is composed of four main layers; the retinal pigment epithelium (RPE), an outer layer consisting of photoreceptor rod and cone cells, a layer of interneurons, and a layer of ganglion cells. Photoreceptor cells contain the visual pigment rhodopsin that transduces light into an electrical signal. Like the worm gonad and mammalian testis, cells of the retina communicate and interact closely with one another. The most striking cell-to-cell interaction is that of the RPE cells and photoreceptors. The outer segments of the photoreceptors are in direct contact with and surrounded by the apical membrane of the RPE (Fig. 4).

The close interaction between the RPE and photoreceptors is essential for rod and cone cell function and survival. RPE cells provide nutritional support to photoreceptors. They also play a critical role in photoreceptor renewal. Rhodopsin is contained within membrane-bound discs that are shed continually from the tips of the photoreceptors and replaced with newly synthesized ones. The RPE cells phagocytose and degrade the shed discs. In ClC-2 knockout mice, the retina undergoes progressive degeneration shortly after birth and adult mice exhibit a complete loss of photoreceptor cells (3).

A role for ClC-2 in intercellular signaling between RPE and photoreceptors seems unlikely since gap junctions do not appear to couple these cells (5). However, ClC-2 is expressed throughout the retina (3,6), and there is extensive gap junction coupling between photoreceptor cells themselves and between various neurons (5). It is conceivable that ClC-2 plays an intercellular signaling role between these cells that is important for the development and maintenance of the photoreceptors. As suggested earlier for Sertoli cells, ClC-2 expressed in RPE cells could also modulate the phagocytic activity of the epithelium. Disruption of phagocytosis in the RPE can lead to complete retinal degeneration (15).

	Conclusions

Top Introduction ClC anion channels: a... ClC biology in C.... Regulation and physiological... Of mice and worms Conclusions References

 
Nematodes are estimated to have diverged from other metazoans 600–1,200 million years ago (1). Why have the biophysical and structural properties of CLH-3 and ClC-2 been conserved over such vast evolutionary distances? Studies in mice and worms indicate that both channels play important roles in tissues in which heterologous cell-to-cell interactions and communication are necessary for normal physiological functioning.

Despite the new insights into CLH-3 and ClC-2, we still do not know the precise roles of these channels in the worm gonad and mouse seminiferous tubule and retina. In addition, the new findings have raised new questions and underscored old ones. CLH-3 expression appears to be restricted to the C. elegans oocyte, excretory cell (the worm "kidney"), certain neurons and muscle cells, uterine cells, and intestinal epithelial cells (14,17,18). In mammals, ClC-2 has a very broad tissue distribution (19). What other physiological roles do these channels play? A number of studies suggest that ClC-2 and CLH-3 do not contribute significantly to volume regulation in native cells and tissues. Why are the channels regulated by cell volume changes then? CLH-3 is activated in the worm oocyte during meiotic cell cycle progression (17). Interestingly, ascidian embryos express an inwardly rectifying Cl^- current strikingly similar to CLH-3 and ClC-2 that is activated by cell swelling and hyperpolarization. The physiological functions and molecular identity of the ascidian channel are unknown, but current amplitude increases nearly 10-fold during mitotic cell cycle progression (2). Is mammalian ClC-2 regulated by cell cycle events? If so, what physiological roles does such regulation play? What are the signaling pathways that activate CLH-3 and ClC-2, and what protein partners interact with and regulate these channels?

"Sertoli cells control development of germ cells into spermatozoa by direct, cell-to-cell physical interaction...."

Biology is rarely reinvented by natural selection. Instead, natural selection takes a working plan and modifies it. Addressing complex physiological problems in a less complex model organism that is genomically defined and genetically tractable and in which it is more straightforward and economical to manipulate gene function is a rational and powerful experimental strategy. C. elegans and other model organisms will undoubtedly continue to provide novel insights into the functional genomics of anion channel physiology as well as numerous other basic biological problems.

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	Acknowledgments

 
I thank Drs. Robert Putnam and Kevin Foskett for critical reading of the manuscript and for many helpful suggestions.

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants R01-DK-51610 and P01-DK-58212.

	References

Top Introduction ClC anion channels: a... ClC biology in C.... Regulation and physiological... Of mice and worms Conclusions References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Strange, K. Search for Related Content PubMed PubMed Citation Articles by Strange, K.