Apoptosis and Development (eBook)

Hermann Steller (Herausgeber)

eBook Download: EPUB

2015 | 1. Auflage
388 Seiten
Elsevier Science (Verlag)
978-0-12-409598-4 (ISBN)

Infos

Apoptosis and Development, the latest volume of Current Topics in Developmental Biology continues the legacy of this premier serial with quality chapters authored by leaders in the field. This volume covers research methods in apoptosis and development, and includes sections on such topics as the non-lethal role of apoptotic proteins and germ line cell death in Drosophila. - Continues the legacy of this premier serial with quality chapters authored by leaders in the field - Includes descriptions of the most recent advances in the field - Covers research methods in apoptosis and development, and includes sections on such topics as the non-lethal role of apoptotic proteins and germ line cell death in Drosophila

Textauszug

Chapter One

Cell Death in C. elegans Development

Jennifer Zuckerman Malin; Shai Shaham1    Laboratory of Developmental Genetics, The Rockefeller University, New York, USA
1 Corresponding author: email address: [e-mail]

Abstract

Cell death is a common and important feature of animal development, and cell death defects underlie many human disease states. The nematode Caenorhabditis elegans has proven fertile ground for uncovering molecular and cellular processes controlling programmed cell death. A core pathway consisting of the conserved proteins EGL-1/BH3-only, CED-9/BCL2, CED-4/APAF1, and CED-3/caspase promotes most cell death in the nematode, and a conserved set of proteins ensures the engulfment and degradation of dying cells. Multiple regulatory pathways control cell death onset in C. elegans, and many reveal similarities with tumor formation pathways in mammals, supporting the idea that cell death plays key roles in malignant progression. Nonetheless, a number of observations suggest that our understanding of developmental cell death in C. elegans is incomplete. The interaction between dying and engulfing cells seems to be more complex than originally appreciated, and it appears that key aspects of cell death initiation are not fully understood. It has also become apparent that the conserved apoptotic pathway is dispensable for the demise of the C. elegans linker cell, leading to the discovery of a previously unexplored gene program promoting cell death. Here, we review studies that formed the foundation of cell death research in C. elegans and describe new observations that expand, and in some cases remodel, this edifice. We raise the possibility that, in some cells, more than one death program may be needed to ensure cell death fidelity.

Keywords

Cell death

C. elegans

Apoptosis

Nonapoptotic cell death

Linker cell

1 Introduction

Cell death is a widespread process that is essential for life. Tissue sculpting, organ morphogenesis, and organ size control are but a few of the developmental events that integrally utilize programmed cell death to generate a functioning adult animal. It is therefore not surprising that many things go wrong when cell death goes awry (Fuchs & Steller, 2011). Indeed, neurodegeneration and tumorigenesis, disease states against which armies of researchers have been amassed, result from too much or too little cell culling, respectively (Hanahan & Weinberg, 2011; Youle & van der Bliek, 2012). While the hypothesis that cell death is a regulated phenomenon in animal development was first experimentally addressed in vertebrates (Hamburger & Levi-Montalcini, 1949) and insects (Lockshin & Williams, 1965), the first systematic studies aimed at deciphering the molecular program promoting cell demise employed the free-living soil nematode Caenorhabditis elegans (Horvitz, 2003). Early observations of the cellular complement of adult C. elegans revealed little variation in the number and position of cells between individuals of similar ages, leading to the proposal that cell lineage in this animal may be invariant. This prediction was largely borne out by taking advantage of the transparent cuticle of the animal to observe cell divisions in vivo (Kimble & Hirsh, 1979; Sulston, Albertson, & Thomson, 1980; Sulston & Horvitz, 1977; Sulston, Schierenberg, White, & Thomson, 1983). This heroic effort culminated in a complete cell lineage tree documenting a generally predictable pattern of divisions that generate adult somatic tissue from the zygote. These studies demonstrated that precisely 1090 and 1178 somatic cells must be generated to produce a C. elegans hermaphrodite and male, respectively.

Among the generated cells, a small but substantial set (~ 12%) are eliminated. These cells become refractile under differential interference contrast (DIC) optics (Fig. 1), acquire a rounded morphology, and eventually disappear. Ultrastructural studies reveal that these dying cells are engulfed by neighboring cells (Sulston et al., 1983), and possess characteristics of apoptotic cell death, such as condensed nuclear chromatin, and reduced cytoplasmic volume (Shaham & Horvitz, 1996b; Sulston et al., 1983) (Fig. 1). Like the lineage itself, these cell death events are essentially invariant between individuals and target the same cells at the same time in development. In the hermaphrodite and male, 131 and 147 somatic cells are eliminated, respectively. Subsequent studies demonstrated that cell death is highly prevalent during germline development and maintenance, with roughly 50% of female meiosis products succumbing to apoptosis (Gumienny, Lambie, Hartwieg, Horvitz, & Hengartner, 1999). Developmental death of germ cells in C. elegans differs from somatic cell death in that the identities of dying cells are not ascribed to their lineage (Gumienny et al., 1999; Sulston et al., 1983). C. elegans therefore offers two arenas for understanding cell death control: one in which cell death and lineage are tightly coupled, and one in which stochastic processes apparently determine life and death. Studies of the former revealed a core pathway controlling apoptotic cell death from C. elegans to mammals.

Figure 1 Apoptotic developmental cell death in C. elegans. (A) Differential interference contrast (DIC) image of a dying cell (arrow) in a developing embryo. Scale bar, 2.5 μm. (B) Electron micrograph of a dying embryonic cell. Note dark staining, condensed chromatin (asterisk) within the nucleus and shrunken cytoplasm. Arrowhead, nuclear envelope. Scale bar, 400 nm. (C) DIC image of dying cells in the developing gonad (arrows). (D) Fluorescence image of animal in (C) stained with the cell death marker SYTO12. Scale bar, 8 μm.

Here, we describe these key components and their interactions and explore current understanding of the lineage-dependent mechanisms that trigger the activation of these killer genes and proteins. We also discuss a group of genes important for the clearance of dying cells and their relation to cell death execution and delve into a number of mysteries that remain unanswered and which have the potential to expand and modify our understanding of why and how cells die. We end by describing a novel nonapoptotic C. elegans cell death program that promotes dismantling of the male-specific linker cell.

2 Core Apoptosis Regulators in C. elegans

Most cell death in C. elegans is controlled by the proteins CED-3, CED-4, CED-9, and EGL-1, whose functions and interactions have been worked out in some detail (Fig. 2). All four components of this canonical cell death pathway are conserved across disparate animal species, but are apparently absent from bacteria, fungi, and plants. Thus, it is likely that this pathway arose early on in the animal lineage.

Figure 2 Apoptotic cell death control in C. elegans. Core cell death components (black) interact with a variety of regulators (blue (gray in the print version)) in different cells (white). Only cells for which direct control of the core apoptotic pathway is established are shown.

2.1 CED-3/Caspase

The most downstream core component of the apoptotic cell death pathway is the protein CED-3, encoded by the ced-3 gene. The role of ced-3 in cell death was initially revealed from genetic studies. Animals mutant for the gene ced-1 (see below) accumulate unengulfed cell corpses during development that are easily detectable using DIC microscopy. A suppressor screen for animals lacking these corpses identified the recessive mutant ced-3(n717), in which most cells fated to die fail to do so. Characterization of the mutant revealed widespread inhibition of cell death, resulting in animals with extra cells (Ellis & Horvitz, 1986). While lineage studies suggest that few, if any, of these extra cells divide (Hoeppner, Hengartner, & Schnabel, 2001), some are able to differentiate (Shaham & Bargmann, 2002), incorporate into neural circuits (White, Southgate, & Thomson, 1991), and even substitute for their surviving sister cells, if those are experimentally ablated (Avery & Horvitz, 1987). ced-3 mutant animals are alive, suggesting that at least under laboratory conditions cell death is not essential (Ellis & Horvitz, 1986). However, some ced-3 animals exhibit defects in chemotaxis to attractive odors, and some exhibit pronounced developmental delay (Ellis, Yuan, & Horvitz, 1991), suggesting that in the wild, cell death likely confers a survival advantage.

The CED-3 protein is a founding member, together with mammalian caspase-1, of the caspase family of proteases (Yuan, Shaham, Ledoux, Ellis, & Horvitz, 1993). Active CED-3 is derived from a precursor that is cleaved to generate three fragments. The N-terminal fragment, which has sequence homology to caspase recruitment domains (CARD), is not required for protease...

Produkt-Details

• Erscheint lt. Verlag: 5.10.2015
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Allgemeines / Lexika
• Themenwelt: Naturwissenschaften ► Biologie ► Biochemie
• Themenwelt: Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Zellbiologie
• ISBN-10: 0-12-409598-4 / 0124095984
• ISBN-13: 978-0-12-409598-4 / 9780124095984