whole_HaasMatildaAnn2006_thesis.pdf (15.63 MB)
The role of the ezrin-radixin-moesin (ERM) proteins in development and post-injury responses of central nervous system neurons
thesisposted on 2023-05-26, 20:54 authored by Haas, MA
The ezrin-radbdn-moesin (ERM) family of proteins mediate diverse cytoskeletal processes, such as cell adhesion and morphology, as well as cell migration. These functions have primarily been elucidated in non-neuronal cell phenotypes, with only limited data pertaining to a role for ERM proteins in CNS neurons. The few studies examining ERM functions in neurons indicate that they contribute to important aspects of developmental neuron growth and morphogenesis; processes that must be precisely executed for the establishment of appropriate connectivity during brain development. Further alluding to their potential importance in the CNS was the identification of ezrin as a binding partner of the developmentally crucial cell adhesion molecule (CAM) L1. After completion of brain development, the mature CNS has very little capacity for regeneration and functional recovery following injury, partly because upon maturation neurons lose their intrinsic ability for substantial growth, but mainly because the mature nervous system environment is inhibitory to growth, particularly following traumatic injury. Therefore, a current and widely accepted theory is that recapitulation of aspects of CNS development is required for regeneration to occur in the more mature nervous system. Thus, investigation of developmentally significant proteins may provide clues as to the requirements for more mature CNS neurons to mount a regenerative response. This thesis investigated ERM protein function in CNS neurons, both during development and regeneration, with investigations focussed on ERM proteins' binding relationship with L1. ERM proteins were specifically expressed during early neuronal morphogenesis, localised to areas associated with motility and growth, and they co-localised with L1, particularly in the axonal growth cone. Perturbation of ERM proteins function utilising transfection of a dominant negative form of ezrin implicated ERMs in multiple aspects of development, including neurite initiation and outgrowth, growth cone morphology, neurite branching and neuron migration. Investigation of ERM function in models of injury to mature neurons demonstrated a re-expression of ERM proteins, potentially to participate in regenerative attempts, including neurite initiation and outgrowth, as well as post-injury neuron motility. Interrupting ERM activation using an inhibitor of Rho kinase significantly perturbed many of these developmental and post-injury functions, confirming a role for Rho kinase in ERM activation. These results show that ERM proteins play significant roles in aspects of neuronal growth and morphology in both developing and regenerating CNS neurons. Furthermore, elucidation of the roles of ERM proteins and L1 show that common mechanisms are required for developmental and regenerative nervous system growth, which is important or uncovering potential mechanisms of regenerative growth, and identifying therapeutic targets for encouraging post-injury regeneration.
Rights statementCopyright 2006 the author - The University is continuing to endeavour to trace the copyright owner(s) and in the meantime this item has been reproduced here in good faith. We would be pleased to hear from the copyright owner(s). Chapter 5 appears to be the equivalent of the pre-peer reviewed version of the following article: Haas, M. A., Chuckowree, J. A., Chung, R. S., Vickers, J. C., Dickson, T. C. (2007), Identification and characterization of a population of motile neurons in long-term cortical culture, Cell motility and the cytoskeleton, 64(4), 274‚Äö-287, which has been published in final form at http://dx.doi.org/10.1002/cm.20182 This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. Chapter 6 appears to be the equivalent of the pre-peer reviewed version of the following article: Haas, M. A., Vickers, J. C., Dickson, T. C. (2007), Rho kinase activates ezrin-radixin-moesin (ERM) proteins and mediates their function in cortical neuron growth, morphology and motility in vitro, Journal of neuroscience research, 85(10), 34‚Äö-46. which has been published in final form at http://dx.doi.org/10.1002/jnr.21102 This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.