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Early during development neurons project small filamentous processes, axons and dendrites, that extend and eventually connect with other cells and tissues. These processes can grow over long distances and allow for transmission of information between cells. The proper functioning of our nervous system is dependent on these same processes correctly navigating to specific end targets. This is achieved through guidance cues in the environment which interact with receptors on the extending processes allowing them to be steered in the correct direction. Unfortunately, due to the high complexity of most vertebrate nervous systems our understanding of how axons and dendrites use these cues to navigate is still very limited. The aim of this thesis was to discover novel genes regulating axon guidance to shine additional light on how axons navigate during development. Normally axons of the ventral nerve cord in the nematode Caenorhabditis elegans are invariably sorted asymmetrically. Animals with mutations impacting function in individual axon guidance signaling pathways show no or only very low penetrance of disruption of VNC asymmetry. Here genetic screens successfully isolated four mutants in which asymmetry between major longitudinal axon tracts is disrupted. One of these four mutants include a novel allele of the gene col-99 which encodes a previously uncharacterized transmembrane collagen with vertebrate homologs. Detailed characterization of animals lacking COL-99 revealed widespread axon guidance defects impacting longitudinal and lateral axon navigation of a variety of neurons. Of the remaining three mutants two were found to be alleles of unc-52 and unc-34, both previously characterised for roles in axon guidance, while the final mutation remains unidentified. Disruption of any one signaling pathway does not lead to penetrant VNC asymmetry defects suggesting redundancy between parallel signaling pathways here. To better understand how signaling pathways of multiple guidance cues may converge to control guidance at choice points single mutants were crossed into a nid-1 null mutant background and VNC asymmetry phenotypes examined. Previously nid-1 was found to substantially enhance navigation defects of the VNC pioneering neuron AVG when crossed into mutants showing a low penetrance of AVG navigation defects. Double mutants with nid-1 saw defect penetrance significantly increase in several cases indicating parallel signaling pathways. Combination of mutants into triple and quadruple mutant strains showed that UNC-6, SAX-3, and COL-99 represent members of parallel signaling pathways acting redundantly to guide axons in establishment of asymmetry which in addition depends on basement membranes components, including EPI-1. Thus multiple axon guidance signaling pathways, acting in tandem, ensure correct guidance and segregation of axons at the anterior choice point of the VNC establishing VNC asymmetry.
The hallmark of the nervous system is its ability to process information. This unique feature relies on proper establishment of the entire network of neuronal connections. Axon guidance is one of the early developmental processes that are essential for establishing functional neuronal connections throughout the nervous system. The goal of my work is to understand the molecular mechanisms of axon guidance and its implications in human disorders. During axon guidance the growing axon has to constantly regulate its receptors in order to properly sense concentration differences across a gradient set by a guidance cue. My results showed that the axon guidance signaling molecule MAX-1 is SUMOylated by its interacting partner GEI-17 and regulates UNC-5 receptor through APB-3 containing AP-3 complex in Caenorhabditis elegans motor neurons. The data collected from my studies lead to a model that MAX-1 and APB-3 signaling pathway modulate the dynamic trafficking of axon guidance receptor UNC-5 when axon is guided across a concentration gradient. Defects in neuronal connectivity of the brain are well documented among schizophrenia patients. Although the schizophrenia susceptibility gene Disrupted-in-Schizophrenia 1 (DISC1) has been implicated in various neurodevelopmental processes, its role in regulating axonal connections remains elusive. Using a relatively simple and well-characterized Caenorhabditis elegans motor neurons system, I established a heterologous DISC1 transgenic model to investigate whether DISC1 regulates axon guidance during development. My results revealed a previously unknown function of DISC1 to shape axonal connectivity in the developing nervous system by exploiting the TRIO-RAC-PAK signaling pathway.
The interaction between biology and evolution has been the subject of great interest in recent years. Because evolution is such a highly debated topic, a biologically oriented discussion will appeal not only to scientists and biologists but also to the interested lay person. This topic will always be a subject of controversy and therefore any breaking information regarding it is of great interest.The author is a recognized expert in the field of developmental biology and has been instrumental in elucidating the relationship between biology and evolution. The study of evolution is of interest to many different kinds of people and Genomic Regulatory Systems: In Development and Evolution is written at a level that is very easy to read and understand even for the nonscientist. * Contents Include* Regulatory Hardwiring: A Brief Overview of the Genomic Control Apparatus and Its Causal Role in Development and Evolution * Inside the Cis-Regulatory Module: Control Logic and How the Regulatory Environment Is Transduced into Spatial Patterns of Gene Expression* Regulation of Direct Cell-Type Specification in Early Development* The Secret of the Bilaterians: Abstract Regulatory Design in Building Adult Body Parts* Changes That Make New Forms: Gene Regulatory Systems and the Evolution of Body Plans
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
Progress in developmental neurobiology and advances in (neuro) genetics have been spectacular. The high resolution of modern imaging techniques applicable to developmental disorders of the human brain and spinal cord have created a novel insight into the developmental history of the central nervous system (CNS). This book provides a comprehensive overview of the development of the human CNS in the context of its many developmental disorders. It provides a unique combination of data from human embryology, animal research and developmental neuropathology, and there are more than 400 figures in over a hundred separate illustrations.
Invertebrates have proven to be extremely useful model systems for gaining insights into the neural and molecular mechanisms of sensory processing, motor control and higher functions such as feeding behavior, learning and memory, navigation, and social behavior. A major factor in their enormous contributions to neuroscience is the relative simplicity of invertebrate nervous systems. In addition, some invertebrates, primarily the molluscs, have large cells, which allow analyses to take place at the level of individually identified neurons. Individual neurons can be surgically removed and assayed for expression of membrane channels, levels of second messengers, protein phosphorylation, and RNA and protein synthesis. Moreover, peptides and nucleotides can be injected into individual neurons. Other invertebrate model systems such as Drosophila and Caenorhabditis elegans offer tremendous advantages for obtaining insights into the neuronal bases of behavior through the application of genetic approaches. The Oxford Handbook of Invertebrate Neurobiology reviews the many neurobiological principles that have emerged from invertebrate analyses, such as motor pattern generation, mechanisms of synaptic transmission, and learning and memory. It also covers general features of the neurobiology of invertebrate circadian rhythms, development, and regeneration and reproduction. Some neurobiological phenomena are species-specific and diverse, especially in the domain of the neuronal control of locomotion and camouflage. Thus, separate chapters are provided on the control of swimming in annelids, crustaea and molluscs, locomotion in hexapods, and camouflage in cephalopods. Unique features of the handbook include chapters that review social behavior and intentionality in invertebrates. A chapter is devoted to summarizing past contributions of invertebrates to the understanding of nervous systems and identifying areas for future studies that will continue to advance that understanding.
Escherichia coli, commonly referred to as E. coli, has been the organism of choice for molecular genetics for decades. Its machinery and mobile behavior is one of the most fascinating topics for cell scientists. Scientists and engineers, not trained in microbiology, and who would like to learn more about living machines, can see it as a unique example. This cross-disciplinary monograph covers more than thirty years of research and is accessible to graduate students and scientists alike.