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Fundamental to our understanding about the function of the visual system is a basic knowledge of the structural components of neurons that comprise the circuit. The goal of the work described here aims to elucidate the structural, developmental, and molecular architecture of retinal ganglion cells (RGCs), using the mouse as a model system. I address three fundamental questions regarding synaptic specificity. First, do RGCs, whose dendrites are hallmarks of laminar specificity within the retina, also display laminar specificity of their axon terminals in the brain? To test this, I survey the axon terminal morphologies of different RGC subtypes and show that much like their dendrites, the axon terminals also display laminar specificity within the superior colliculus (SC). Second, what are the structural changes that take place over development that result in targeting of RGC axons to their proper target cells in the dorsal lateral geniculate (dLGN)? By observing the structural development of a single subtype of RGC I demonstrate that, in the retinogeniculate system, a dominant mechanism of synapse refinement is the growth and redistribution of synapses along the axon arbor. Finally, what are the molecular mechanisms that mediate laminar specificity? Sidekicks are synaptic cell adhesion molecules that are thought to mediate laminar specificity of dendrites in the chick retina. Functional studies would benefit from using mice, where genetic tools are more readily available. I show that Sidekick1 and 2 are localized to restricted sublaminae within the mouse retina, and is also present in other sensory neurons. The expression analysis is a necessary first step, and sets the foundation for studying the functional role of Sidekicks in ongoing work with loss-of-function mouse models.
Glaucoma, just as many other neurodegenerative diseases, triggers neuronal death and remained incurable, hence representing a heavy burden for the society. Therefore, there is a critical need for developing new therapeutic strategies to delay the progression of and, ultimately, cure neurological conditions. For decades, neuroscientists studying injuries and diseases of the CNS have largely focused on understanding the mechanisms of axon degeneration to identify new targets for axonal protection and regeneration. But recent data indicates that dendritic deficits represent an early feature of neurodegeneration, a phenomenon now called dendritic pathology and playing a key role in the pathogenesis of neurodegenerative diseases including glaucoma. Because dendrites are essential structures for neuronal communication and function, it is therefore crucial to protect or restore connectivity as well as axons of surviving neurons to improve patients' condition. In spite of this, the ability of injured neurons to regenerate dendrites remains largely ignored. The central hypothesis of the thesis is that: i) adult CNS neurons can regrow their dendrites after axonal injury, and ii) the identification of underlying signalling pathways would offer new therapeutic avenues to slow or prevent retinal ganglion cell death during ocular neuropathies such as glaucoma. In the first part of my thesis, I demonstrated that mammalian neurons are endowed with the ability to restore their dendritic arbor and synaptic connectivity. Using adult transgenic mice subjected to optic nerve axotomy, we have shown that retinal ganglion cells (RGCs) rapidly undergo dendritic shrinkage before cell death or axonal damage become visible. We also demonstrated that daily insulin, administered topically (eye drops) or systemically (intraperitoneal) after dendritic arbour shrinkage and prior to neuronal loss results in a robust regeneration of dendrites and successful reconnection with presynaptic targets. Moreover, insulin-mediated restoration of dendritic arbors extended neuronal survival and rescued lighttriggered retinal responses. Targeted loss-of-function experiments using siRNAs revealed that insulin-dependent regeneration requires both the activity of both mTOR complexes, mTORC1 and mTORC2 which act synergistically, mTORC1 promoting new dendritic branching to restore arbor complexity, while mTORC2 drives dendritic process elongation. In the second study presented in my thesis, we showed for the first time that morgana, a chaperone protein downstream of mTORC2, is expressed by RGCs and severely downregulated soon after axonal injury. We also demonstrate that morgana is required for successful insulinmediated regeneration of RGC dendrites and neuroprotection. Morgana specific knockdown using siRNA designed against morgana resulted in substantial alterations of dendrite elongation, without changes in arbor complexity. Further, we showed that AAV-mediated rescue of morgana expression selectively in RGCs promoted striking regeneration of dendrites and synapses. Hence, our findings identified a new role for morgana in the regulation of dendritic arbor morphology in adult mammalian neurons Collectively, the findings presented in this thesis contribute to a better understanding of the pathological mechanisms underlying RGC dendritic pathology and identified promising targets for the development of novel neuroprotective treatments for neurodegenerative diseases such as glaucoma.
This collection of fifteen previously published papers, some of them not widely available, have been carefully chosen and annotated by Rall's colleagues and other leading neuroscientists.
This advanced text, first published in 2006, takes a developmental approach to the presentation of our understanding of how vertebrates construct a retina. Written by experts in the field, each of the seventeen chapters covers a specific step in the process, focusing on the underlying molecular, cellular, and physiological mechanisms. There is also a special section on emerging technologies, including genomics, zebrafish genetics, and stem cell biology that are starting to yield important insights into retinal development. Primarily aimed at professionals, both biologists and clinicians working with the retina, this book provides a concise view of vertebrate retinal development. Since the retina is 'an approachable part of the brain', this book will also be attractive to all neuroscientists interested in development, as processes required to build this exquisitely organized system are ultimately relevant to all other parts of the central nervous system.
Development of the Visual System presents a selection of current studies that clearly illustrate principles of visual system development. These range from retinal development in fish and frogs to the effects of abnormal visual experience on the primary visual cortex of the cat. The book is unique in addressing four specific and fundamental aspects of development: cell lineage and cell fate, specificity and targeting of axons, specification of visual cortex, and correlates of the critical period. Encompassing technical advances in cellular and molecular biology and in video imaging and microscopy, contributions in each of these areas provide new information at the cellular and molecular levels to complement the now classic descriptions of visual development previously available at the level of neural systems.ContributorsKaren L. Allendoerfer, David M. Altshuler, Antonella Antonini, Seymour Benzer, Edward M. Callaway, Constance L. Cepko, Hollis T. Cline, Max S. Cynader, N. W. Daw, Scott E. Fraser, K. Fox, Eckhard Friauf, Anirvan Ghosh, R. W. Guillery, William A. Harris, Christine E. Holt, Lawrence C. Katz, Susan McConnell, Pamela A. Raymond, Thomas A. Reh, Carla J. Shatz, Michael P. Stryker, Claudia A. 0. Stuermer, Mriganka Sur, David L. Turner, T. N. Wiesel
This comprehensive guide to current research captures the first wave of studies in the field, with fifty-nine chapters by leading scholars that demonstrate the usefulness of mouse models as a bridge between experimental and clinical research. The opening chapters introduce the mouse as a species and research model, discussing such topics as the mouse's evolutionary history and the mammalian visual system. Subsequent sections explore more specialized subjects, considering optics, psychophysics, and the visual behaviors of mice; the organization of the adult mouse eye and central visual system; the development of the mouse eye (including comparisons to human development); the development and plasticity of retinal projections and visuotopic maps; mouse models for human eye disease (including glaucoma and cataracts); and the application of advanced genomic technologies (including gene therapy and genetic knockouts) to the mouse visual system. Readers of this reference will see th.
Intracellular cell signaling is a well understood process. However, extracellular signals such as hormones, adipokines, cytokines and neurotransmitters are just as important but have been largely ignored in other works. Aimed at medical professionals and pharmaceutical specialists, this book integrates extracellular and intracellular signalling processes and offers a fresh perspective on new drug targets.