GLD-4-Mediated Translational Activation Regulates the Size of the Proliferative Germ Cell Pool in the Adult C. elegans Germ Line

To avoid organ dysfunction as a consequence of tissue diminution or tumorous growth, a tight balance between cell proliferation and differentiation is maintained in metazoans. However, cell-intrinsic gene expression mechanisms controlling adult tissue homeostasis remain poorly understood. By focusing on the adult Caenorhabditis elegans reproductive tissue, we show that translational activation of mRNAs is a fundamental mechanism to maintain tissue homeostasis. Our genetic experiments identified the Trf4/5-type cytoplasmic poly(A) polymerase (cytoPAP) GLD-4 and its enzymatic activator GLS-1 to perform a dual role in regulating the size of the proliferative zone. Consistent with a ubiquitous expression of GLD-4 cytoPAP in proliferative germ cells, its genetic activity is required to maintain a robust proliferative adult germ cell pool, presumably by regulating many mRNA targets encoding proliferation-promoting factors. Based on translational reporters and endogenous protein expression analyses, we found that gld-4 activity promotes GLP-1/Notch receptor expression, an essential factor of continued germ cell proliferation. RNA-protein interaction assays documented also a physical association of the GLD-4/GLS-1 cytoPAP complex with glp-1 mRNA, and ribosomal fractionation studies established that GLD-4 cytoPAP activity facilitates translational efficiency of glp-1 mRNA. Moreover, we found that in proliferative cells the differentiation-promoting factor, GLD-2 cytoPAP, is translationally repressed by the stem cell factor and PUF-type RNA-binding protein, FBF. This suggests that cytoPAP-mediated translational activation of proliferation-promoting factors, paired with PUF-mediated translational repression of differentiation factors, forms a translational control circuit that expands the proliferative germ cell pool. Our additional genetic experiments uncovered that the GLD-4/GLS-1 cytoPAP complex promotes also differentiation, forming a redundant translational circuit with GLD-2 cytoPAP and the translational repressor GLD-1 to restrict proliferation. Together with previous findings, our combined data reveals two interconnected translational activation/repression circuitries of broadly conserved RNA regulators that maintain the balance between adult germ cell proliferation and differentiation.     

Mitochondrial Regulation of Cell Death

Although required for life, paradoxically, mitochondria are often essential for initiating apoptotic cell death. Mitochondria regulate caspase activation and cell death through an event termed mitochondrial outer membrane permeabilization (MOMP); this leads to the release of various mitochondrial intermembrane space proteins that activate caspases, resulting in apoptosis. MOMP is often considered a point of no return because it typically leads to cell death, even in the absence of caspase activity. Because of this pivotal role in deciding cell fate, deregulation of MOMP impacts on many diseases and represents a fruitful site for therapeutic intervention. Here we discuss the mechanisms underlying mitochondrial permeabilization and how this key event leads to cell death through caspase-dependent and -independent means. We then proceed to explore how the release of mitochondrial proteins may be regulated following MOMP. Finally, we discuss mechanisms that enable cells sometimes to survive MOMP, allowing them, in essence, to return from the point of no return.In most organisms, mitochondria play an essential role in activating caspase proteases through a pathway termed the mitochondrial or intrinsic pathway of apoptosis. Mitochondria regulate caspase activation by a process called mitochondrial outer membrane permeabilization (MOMP). Selective permeabilization of the mitochondrial outer membrane releases intermembrane space (IMS) proteins that drive robust caspase activity leading to rapid cell death. However, even in the absence of caspase activity, MOMP typically commits a cell to death and is therefore considered a point of no return (Fig. 1). Because of this pivotal role in dictating cell fate, MOMP is highly regulated, mainly through interactions between pro- and antiapoptotic members of the Bcl-2 family. In this article, we begin by discussing how mitochondria may have evolved to become central players in apoptotic cell death. We then provide an overview of current models addressing the mechanics of MOMP, outlining how this crucial event leads to cell death through both caspase-dependent or -independent mechanisms. Finally, we discuss how caspase activity may be regulated post-MOMP and define other processes that allow cells to survive MOMP and, in effect, return from the point of no return.Open in a separate windowFigure 1.Mitochondrial regulation of cell death. Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP) can lead to caspase-dependent apoptosis (left) or caspase-independent cell death (right). Following MOMP, soluble proteins are released from the mitochondrial intermembrane space into the cytoplasm. Cytochrome c binds to monomeric Apaf-1 leading to its conformational change and oligomerization. Procaspase-9 is recruited to heptameric Apaf-1 complexes forming the apoptosome. This leads to activation of caspase-9 and, through caspase-9-mediated cleavage, activation of the executioner caspases-3 and -7. Release of Smac and Omi from the mitochondrial intermembrane space facilitates caspase activation by neutralizing the caspase inhibitor XIAP. MOMP can also lead to nonapoptotic cell death through a gradual loss of mitochondrial function and/or release of mitochondrial proteins that kill the cell in a caspase-independent manner.     

The C. elegans TPR Containing Protein,TRD-1, Regulates Cell Fate Choice in the Developing Germ Line and Epidermis

Correct cell fate choice is crucial in development. In post-embryonic development of the hermaphroditic Caenorhabitis elegans, distinct cell fates must be adopted in two diverse tissues. In the germline, stem cells adopt one of three possible fates: mitotic cell cycle, or gamete formation via meiosis, producing either sperm or oocytes. In the epidermis, the stem cell-like seam cells divide asymmetrically, with the daughters taking on either a proliferative (seam) or differentiated (hypodermal or neuronal) fate. We have isolated a novel conserved C. elegans tetratricopeptide repeat containing protein, TRD-1, which is essential for cell fate determination in both the germline and the developing epidermis and has homologs in other species, including humans (TTC27). We show that trd-1(RNAi) and mutant animals have fewer seam cells as a result of inappropriate differentiation towards the hypodermal fate. In the germline, trd-1 RNAi results in a strong masculinization phenotype, as well as defects in the mitosis to meiosis switch. Our data suggests that trd-1 acts downstream of tra-2 but upstream of fem-3 in the germline sex determination pathway, and exhibits a constellation of phenotypes in common with other Mog (masculinization of germline) mutants. Thus, trd-1 is a new player in both the somatic and germline cell fate determination machinery, suggestive of a novel molecular connection between the development of these two diverse tissues.     

Regulation of Ferroptotic Cancer Cell Death by GPX4

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Regulation of C. elegans longevity by specific gustatory and olfactory neurons

The life span of C. elegans is extended by mutations that inhibit the function of sensory neurons. In this study, we show that specific subsets of sensory neurons influence longevity. We find that certain gustatory neurons inhibit longevity, whereas others promote longevity, most likely by influencing insulin/IGF-1 signaling. Olfactory neurons also influence life span, and they act in a distinct pathway that involves the reproductive system. In addition, we find that a putative chemosensory G protein-coupled receptor that is expressed in some of these sensory neurons inhibits longevity. Together our findings imply that the life span of C. elegans is regulated by environmental cues and that these cues are perceived and integrated in a complex and sophisticated fashion by specific chemosensory neurons.     

Regulation of photosensation by hydrogen peroxide and antioxidants in C. elegans

The eyeless C. elegans exhibits robust phototaxis behavior in response to short-wavelength light, particularly UV light. C. elegans senses light through LITE-1, a unique photoreceptor protein that belongs to the invertebrate taste receptor family. However, it remains unclear how LITE-1 is regulated. Here, we performed a forward genetic screen for genes that when mutated suppress LITE-1 function. One group of lite-1 suppressors are the genes required for producing the two primary antioxidants thioredoxin and glutathione, suggesting that oxidization of LITE-1 inhibits its function. Indeed, the oxidant hydrogen peroxide (H₂O₂) suppresses phototaxis behavior and inhibits the photoresponse in photoreceptor neurons, whereas other sensory behaviors are relatively less vulnerable to H₂O₂. Conversely, antioxidants can rescue the phenotype of lite-1 suppressor mutants and promote the photoresponse. As UV light illumination generates H₂O₂, we propose that upon light activation of LITE-1, light-produced H₂O₂ then deactivates LITE-1 to terminate the photoresponse, while antioxidants may promote LITE-1’s recovery from its inactive state. Our studies provide a potential mechanism by which H₂O₂ and antioxidants act synergistically to regulate photosensation in C. elegans.     

细胞死亡的基因调节

GeneRegulationofProgrammedCellDeathYangJianminLiuLianrui(InstituteofGenetics,AcademiaSinica,Beijing100101)细胞死亡与细胞生长、分化和增殖一样是维持生物体平衡的重要环节。它是生命过程一个重要组成部分,只在近年来才引起生物学家和医学家的重视．细胞死亡现象称为Apoptosis,或称Programmedcelldeath（细胞程序化死亡）,也有称为Suicide（细胞自杀现象）。细胞死亡（apoptosis）是在细胞内和细胞外因子的严格控制下～种有步骤有活性的生理性自行消亡过程,正在死亡的细胞形态上发生明显的变化,如胞浆浓缩,原生质膜形…     

Cell proliferation and growth in C. elegans.

The cell division and differentiation events that occur during the development of the nematode Caenorhabditis elegans are nearly identical between different individuals, a feature that distinguishes this organism from larger and more complex metazoans, such as humans and Drosophila. In view of this discrepancy, it might be expected that the regulation of cell growth, division and differentiation in C. elegans would involve mechanisms separate from those utilized in larger animals. However, the results of recent genetic, molecular and cellular studies indicate that C. elegans employs an arsenal of developmental regulatory mechanisms quite similar to those wielded by its arthropod and vertebrate relatives. Thus, the nematode system is providing both novel and complementary insights into the general problem of how growth and patterning events are integrated in development. This review offers a general perspective on the regulation of cell division and growth in C. elegans, emphasizing recent studies of these crucial aspects of development.     

Cell polarity and gastrulation in C. elegans.

Gastrulation in C. elegans embryos involves formation of a blastocoel and the ingression of surface cells into the blastocoel. Mutations in the par-3 gene cause abnormal separations between embryonic cells, suggesting that the PAR-3 protein has a role in blastocoel formation. In normal development, PAR proteins localize to either the apical or basal surfaces of cells prior to blastocoel formation; we demonstrate that this localization is determined by cell contacts. Cells that ingress into the blastocoel undergo an apical flattening associated with an apical concentration of non-muscle myosin. We provide evidence that ingression times are determined by genes that control cell fate, though interactions with neighboring cells can prevent ingression.     

Regulation of sperm activation by SWM-1 is required for reproductive success of C. elegans males

BACKGROUND: Sexual reproduction in animals requires the production of highly specialized motile sperm cells that can navigate to and fertilize ova. During sperm differentiation, nonmotile spermatids are remodeled into motile spermatozoa through a process known as spermiogenesis. In nematodes, spermiogenesis, or sperm activation, involves a rapid cellular morphogenesis that converts unpolarized round spermatids into polarized amoeboid spermatozoa capable of both motility and fertilization. RESULTS: Here we demonstrate, by genetic analysis and in vivo and in vitro cell-based assays, that the temporal and spatial localization of spermiogenesis are critical determinants of male fertility in C. elegans, a male/hermaphrodite species. We identify swm-1 as a factor important for male but not hermaphrodite fertility. We show that whereas in wild-type males, activation occurs after spermatids are transferred to the hermaphrodite, swm-1 mutants exhibit ectopic activation of sperm within the male reproductive tract. This ectopic activation leads to infertility by impeding sperm transfer. The SWM-1 protein is composed of a signal sequence and two trypsin inhibitor-like domains and likely functions as a secreted serine protease inhibitor that targets two distinct proteases. CONCLUSIONS: These findings support a model in which (1) proteolysis acts as an important in vivo trigger for sperm activation and (2) regulating the timing of proteolysis-triggered activation is crucial for male reproductive success. Furthermore, our data provide insight into how a common program of gamete differentiation can be modulated to allow males to participate in reproduction in the context of a male/hermaphrodite species where the capacity for hermaphrodite self-fertilization has rendered them nonessential for progeny production.     

Peroxiredoxins and the Regulation of Cell Death

Cell death pathways such as apoptosis can be activated in response to oxidative stress, enabling the disposal of damaged cells. In contrast, controlled intracellular redox events are proposed to be a significant event during apoptosis signaling, regardless of the initiating stimulus. In this scenario oxidants act as second messengers, mediating the post-translational modification of specific regulatory proteins. The exact mechanism of this signaling is unclear, but increased understanding offers the potential to promote or inhibit apoptosis through modulating the redox environment of cells. Peroxiredoxins are thiol peroxidases that remove hydroperoxides, and are also emerging as important players in cellular redox signaling. This review discusses the potential role of peroxiredoxins in the regulation of apoptosis, and also their ability to act as biomarkers of redox changes during the initiation and progression of cell death.     

Regulation of aging and innate immunity in C. elegans

The free-living soil nematode Caenorhabditis elegans is a versatile model for the study of the genetic regulation of aging and of host-pathogen interactions. Many genes affecting multiple processes, such as neuroendocrine signalling, nutritional sensing and mitochondrial functions, have been shown to play important roles in determining the lifespan of C. elegans. The DAF-2-mediated insulin signalling pathway is the major pathway that regulates aging in this nematode and this role appears universal; neuroendrocrine signalling also affects aging in Drosophila and mice. Recent studies have shown that the innate immune function in C. elegans is modulated by signalling from the TGF-beta-like, the p38 MAPK and the DAF-2 insulin pathways. The requirement for the DAF-2 pathway in modulating aging and immunity suggests that these processes may be linked at the molecular level. It is well known that as humans age, immunosenescence occurs in which there is a general degradation of immune efficiency. However, the molecular mechanisms involved in this process remain unclear. In this review, we discuss the molecular mechanisms that modulate aging and immune response and attempt to suggest molecular links between these two processes.     

植物细胞编程性死亡的调控

细胞编程性死亡（PCD）在植物生长发育及植物对环境的适应性方面起重要作用。文章主要从PCD相关基因,信号转导途径,蛋白酶及核酸酶等方面介绍植物细胞编程性死亡的调控。     

Regulation of chemosensory and GABAergic motor neuron development by the C. elegans Aristaless/Arx homolog alr-1

Mutations in the highly conserved Aristaless-related homeodomain protein ARX have been shown to underlie multiple forms of X-linked mental retardation. Arx knockout mice exhibit thinner cerebral cortices because of decreased neural precursor proliferation, and also exhibit defects in the differentiation and migration of GABAergic interneurons. However, the role of ARX in the observed behavioral and developmental abnormalities is unclear. The regulatory functions of individual homeodomain proteins and the networks in which they act are frequently highly conserved across species, although these networks may be deployed in different developmental contexts. In Drosophila, aristaless mutants exhibit defects in the development of terminal appendages, and Aristaless has been shown to function with the LIM-homeodomain protein LIM1 to regulate leg development. Here, we describe the role of the Aristaless/Arx homolog alr-1 in C. elegans. We show that alr-1 acts in a pathway with the LIM1 ortholog lin-11 to regulate the development of a subset of chemosensory neurons. Moreover, we demonstrate that the differentiation of a GABAergic motoneuron subtype is affected in alr-1 mutants, suggesting parallels with ARX functions in vertebrates. Investigating ALR-1 functions in C. elegans may yield insights into the role of this important protein in neuronal development and the etiology of mental retardation.