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The genetic study of the C. elegans dauer developmental decision has served as an experimental paradigm for understanding how environmental cues influence organismal physiology through evolutionarily conserved neuroendocrine signaling mechanisms. My genetic characterization of the previously isolated daf-28(sa191) mutant that enters dauer constitutively has revealed cell-nonautonomous roles of conserved stress signaling pathways-the Unfolded Protein Response (UPR) and translational control mediated by eIF2[alpha] phosphorylation. While the cell-autonomous functions of these stress-responsive mechanisms in maintaining cellular homeostasis have been examined, their organismal effects on remodeling development and stress responses remain largely unexplored. Chapter II will highlight the hypotheses and approaches that led to identification of the PEK-1/PERK branch of the UPR, functioning in a pair of chemosensory neurons, as a novel regulator of the dauer developmental decision. Chapter III will examine the systemic effects of eIF2[alpha] phosphorylation, downstream of PERK/PEK-1 activation, in the sensory nervous system on larval development and stress responses. Specifically, the identification of the C. elegans translational regulatory factors that function as molecular determinants of cellular and systemic sensitivity to eIF2[alpha] phosphorylation will be described. Subsections of Chapter III and IV will also highlight genes whose functions can modify the organismal effects of the UPR and eIF2[alpha] phosphorylation: these genes are involved in modulation of ER proteostasis or function in the dauer neuroendocrine pathways that interact with the UPR or eIF2[alpha] phosphorylation. Finally, we proceed to show that alterations in the neuronal eIF2[alpha] phosphorylation status may modulate sensory processing to influence diverse physiological outputs, mimicking the effects of starvation or unfavorable microbial environment. Collectively, results from my study indicate that modulation of the UPR and eIF2[alpha]-mediated translational control in the sensory nervous system confers substantial cell-nonautonomous effects on animal physiology. These findings underscore how molecular events underlying cellular homeostasis, which can be perturbed by fluctuating environmental and developmental conditions, may be co-opted to systemically reprogram organismal stress responses in C. elegans.
The Neurobiology of C. elegans assembles together a series of chapters describing the progress researchers have made toward solving some of the major problems in neurobiology with the use of this powerful model organism. The first chapter is an introduction to the anatomy of the C. elegans nervous system. This chapter provides a useful introduction to this system and will help the reader who is less familiar with this system understand the chapters that follow. The next two chapters on learning, conditioning and memory and neuronal specification and differentiation, summarize the current state of the C. elegans field in these two major areas of neurobiology. The remaining chapters describe studies in C. elegans that have provided particularly exciting insights into neurobiology.
An updated edition of the classic Methods in Cell Biology volume 48, this book emphasizes diverse methods and technologies needed to investigate C. elegans, both as an integrated organism and as a model system for research inquiries in cell, developmental, and molecular biology, as well as in genetics and pharmacology. By directing its audience to tried-and-true and cutting-edge recipes for research, this comprehensive collection is intended to guide investigators of C. elegans for years to come. Diverse, up-to-date techniques covered will be useful to the broadening community of C. elegans researchers for years to come Chapters written by leaders in the field Tried and true methods deliver busy researchers a one-stop compendium of essential protocols
The nematode C. elegans is one of the most important model organisms for understanding neurobiology. Its completely mapped neural connectome of 302 neurons and fully characterized and stereotyped development have made it a prototype for understanding nervous system structure, development, and function. Fifty-six out of C. elegans' total of 959 somatic cells are classified as neuroglia. Although research on worm glia has lagged behind studies focused on neurons, there has been a steep upswing in interest during the past decade. Information arising from the recent burst of research on worm glia supports the idea that C. elegans will continue to be an important animal model for understanding glial cell biology. Since the developmental lineage of all cells was mapped, each glial cell in C. elegans is known by a specific name and has research associated with it. We list and describe the glia of the hermaphrodite form of C. elegans and summarize research findings relating to each glial cell. We hope this lecture provides an informative overview of worm glia to accompany the excellent and freely available online resources available to the worm research community.
Comprehensive Overview of Advances in OlfactionThe common belief is that human smell perception is much reduced compared with other mammals, so that whatever abilities are uncovered and investigated in animal research would have little significance for humans. However, new evidence from a variety of sources indicates this traditional view is likely
This book provides new insights into the universality of biological systems in animal reproduction and development by a comparative study of a variety of mechanisms in animals ranging from basal invertebrates to vertebrates, including mammals. Animals accomplish genetic diversity through meiosis and fertilization, and during embryogenesis animals must produce specialized cell types, including germ cells, in accordance with their individual body plan. This series of phenomena is essential to the continuity of life in the animal kingdom, and animals show various reproductive and developmental strategies. This volume, comprising four parts, reviews animal kingdom diversity, including reproductive strategies and germ cell differentiation mechanisms (Part 1), sex determination and differentiation (Part2), the mechanisms of fertilization (Part 3), and body axis formation (Part 4). Readers will find descriptions of the reproduction or development of 180 species, 13 phyla, 35 classes, 74 orders, 117 families, and 151 genera in this book. Of particular interest is the diversity of molecules and mechanisms used to achieve the same biological purpose in different animals. Undergraduates, graduate students, and professional scientists who want a deeper understanding of animal reproductive and developmental mechanisms will find this book to be of great value.
Discrimination among pathogenic and beneficial microbes is essential for host organism immunity and homeostasis. Increasingly, the nervous system of animals is being recognized as an important site of bacterial recognition, but the molecular mechanisms underlying this process remain unclear. Chapter One discusses how the nematode Caenorhabditis elegans can be used to dissect the genetic and neuronal mechanisms that coordinate behavioral responses to bacteria. In Chapter Two, we show that chemosensory detection of two secondary metabolites produced by Pseudomonas aeruginosa modulates a neuroendocrine signaling pathway that promotes C. elegans avoidance behavior. Specifically, secondary metabolites phenazine- I -carboxamide and pyochelin activate a G protein-signaling pathway in the ASJ chemosensory neuron pair that induces expression of the neuromodulator DAF-7/TGF-[beta]. DAF-7, in turn, activates a canonical TGF-P signaling pathway in adjacent interneurons to modulate aerotaxis behavior and promote avoidance of pathogenic P. aeruginosa. This chapter provides a chemical, genetic, and neuronal basis for how the behavior and physiology of a simple animal host can be modified by the microbial environment, and suggests that secondary metabolites produced by microbes may provide environmental cues that contribute to pathogen recognition and host survival. Genetic dissection of neuronal responses to bacteria in C. elegans can also lend insights into neurobiology more generally. In Chapter Three we show that loss of the lithium-sensitive phosphatase bisphosphate 3'-nucleotidase (BPNT-1) results in the selective dysfunction of the ASJ chemosensory neurons. As a result, BPNT- 1 mutants are defective in behaviors dependent on the ASJ neurons, such as pathogen avoidance and dauer exit. Acute treatment with lithium also causes reversible dysfunction of the ASJ neurons, and we show that this effect is mediated specifically through inhibition of BPNT-1. Finally, we show that lithium's selective effect on the nervous system is due in part to the limited expression of the cytosolic sulfotransferase SSU-1 in the ASJ neuron pair. Our data suggest that lithium, through inhibition of BPNT- 1 in the nervous system, can cause selective toxicity to specific neurons, resulting in corresponding effects on behavior of C. elegans. In Chapter Four I discuss the future directions for the genetic dissection of pathogen recognition in C. elegans.
Caenorhabditis Elegans has been a popular model organism for biological research for over thirty years and has been used to investigate many aspects of animal development, for example apoptosis, the Hox genes, signal transduction pathways, and the development of the nervous system. It has recently taken on new importance with the publication of the entire genome sequence in 1998. The first chapter gives all the basic information on C. elegans required to use it: it's natural history, anatomy, life cycle, development, and evolution. Information on how to obtain, grow, and maintain C. elegans for use as a model system is given in Chapter 4. Chapters 2 and 3 describe the genome project and show how to use genome sequence information by searching the database for homologues using different search methods and then how to analyse the search data. The next chapter gives the essential practical details of transformation and common uses for the technique. Chapter 6 covers reverse genetics and describes strategies for gene inactivation that are known to work in C elegans: epigenetic inactivation and mutational germ line inactivation. Chapter 7 is designed to help the user analyse phenotype by microscopy and includes Normaski, fluorescence, 4-dimensional, and electron microscopy. Techniques for studying the neurobiology of C. elegans are given in chapter 8. Chapter 9 describes the three commonly used approaches for studying gene expression and Chapter 10 deals with the common methods of molecular biology essential for gene characterization. C. elegans is not the ideal organism for biochemical studies, but chapter 11 describes several procedures for producing biochemically useful quantities of pure tissues. The final chapter is about conventional genetics and details the standard procedures for selfing and crossing; mutagenesis and mutant screening; characterization of mutants; gene mapping; temperature-shift experiments and mosaic analysis. Caenorhabditis Elegans: A Practical Approach will therefore provide all the background information necessary for use of C. elegans as a model system.
The development and function of the nervous system is under delicate regulation of diverse tissue-derived signals in multi-cellular organisms. In Dr. Nonet's lab, I am using the model organism Caenorhabditis elegans to ask two basic questions: 1) How do different tissues in an organism coordinate to regulate neural functions and behaviors? 2) What controls the development of synapse, the basic unit of the nervous system? These questions divide my dissertation into three parts, with the first two parts related to the first question and the third part to the second question. In the first part of this dissertation, I present work that demonstrates the role of the C. elegans intestine as an endocrine organ in regulating the rhythmic defecation behavior (Chapter 2). The C. elegans defecation behavior consists of three well-coordinated muscle contractions that enable the nematode to expel intestinal contents out to the environment. Genetic and cell biology analyses showed that the early and late muscle contractions involve activities in the intestine and GABAergic neurons (AVL and DVB), respectively, while it remains unclear how the intestinal event is coordinated with later activation of GABAergic neurons. Using molecular genetics and cell biology approaches, we demonstrate that the exocytic protein AEX-4 and proprotein convertase AEX-5 function in the worm intestine to control the defecation motor program. When expressed in the intestine, AEX-5 is secreted into the pseudocoelom, and this secretion is blocked by AEX-4 disruption. Moreover, we show that the G-protein coupled receptor (GPCR) AEX-2 functions in GABAergic neurons to regulate defecation behavior, and it is genetically downstream of intestinal AEX-4 and AEX-5 signals. We also demonstrate that the stimulatory G & alpha; pathway relays the AEX-2 signal in GABAergic neurons. Together, our results provide evidence that the C. elegans intestine is able to modulate neuronal function by secretory signals. In the second part of this dissertation, I present work that demonstrates the role of the C. elegans intestine in modulating the cholinergic neurotransmission (Chapter 3). C. elegans utilizes acetylcholine as a neurotransmitter at its neuromuscular junctions (NMJs) to control muscle contractions and locomotion related behaviors. Using molecular genetics, pharmacological, and physiological approaches, we show that the proprotein convertase AEX-5 is required in the intestine to maintain normal cholinergic transmission in the nematode. In addition, we find that the GPCR AEX-2 functions in the GABAergic neurons to maintain cholinergic transmission level, and the stimulatory G[alpha] pathway is genetically downstream of AEX-2. Interestingly, we find that although both the defecation motor program and the cholinergic transmission modulation involve intestinal signals and neuronal G-protein pathways, they depend on different downstream molecules: while the defecation requires GABA to activate the enteric muscle contraction in the last step of the defecation, the modulation of cholinergic transmission depends on neuropeptide processing enzymes EGL-3 and EGL-21. As GABAergic neurons do not directly synapse on cholinergic neurons in C. elegans, we speculate that the peptide signals act in a paracrine manner on cholinergic neurons. This suggests the C. elegans intestine could function as an endocrine organ to modulate multiple aspects of neuronal functions. In the last part of this dissertation, I focus on the early neural development of C. elegans and I present the preliminary work on the focal adhesion complex molecule ZYX-1 for its role in mechanosensory synapse development (Chapter 4). We cloned the zyx-1 allele from the genetic screen that looked for worms defective in PLM synaptic patch formation. Using time course imaging analysis of fluorescence labeled PLM neurons, we showed that zyx-1 mutants are able to form synapses during early development, while they fail to maintain the synapse to adulthood. In addition, we demonstrated that ZYX-1 acts cell-autonomously in mechanosensory neurons to regulate PLM synapse maintenance. I expect the identification of additional molecular players in the ZYX-1 pathway will shed light onto our understanding of the molecular mechanisms underlying synapse development.