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Axon Initial Segment cytoskeleton, composition and plasticity regulation by Formins

AuthorsZhang, Wei
AdvisorGarrido Jurado, Juan José
Issue Date27-Nov-2019
PublisherUniversidad Autónoma de Madrid
AbstractThe axon initial segment (AIS) is a specialized compartment crucial for generating action potentials and maintaining neuronal polarity. An integrated structure composed of a high concentration of voltage gated ion channels, a specific cytoskeleton architecture, as well as, scaffold proteins like ankyrinG and βIV-spectrin, contributes to these functions. Recent studies have revealed that AIS is dynamically regulated in molecular composition, length and location in response to neuronal activity alterations both in physiological and pathological conditions. Some mechanisms acting on AIS plasticity have been uncovered lately, which include calcium dependent calpain or calcineurin modulation, as well as, modifications of cytoskeleton proteins. However, it is not clear how AIS is regulated in its structure and functions, and which proteins may regulate AIS cytoskeleton. In this study, using pharmacological methods we found that formins modulate AIS maintenance in vitro and in vivo. Formins are a group of proteins involved in cytoskeleton regulation. Currently, 15 formin members are identified in mammals. In neurons, different formins show differential distribution and regulation mechanisms. Only a few studies have revealed that formin members play different roles in neurons, such as axonal and dendritic development, spine morphogenesis and synapse modulation. Regarding brain diseases, some mutations in formin proteins were found in patients suffering mental retardation, Alzheimer’s disease, seizures and schizophrenia, suggesting that formins may play some important roles on neuronal activity. Our study demonstrates that formins inhibition modifies AIS cytoskeleton properties and their associated structural proteins and function. Interestingly, we found that mDia1 is at least one major formin family member that functions both in the AIS assembly and maintenance. mDia1 inhibition or suppression affects AIS length and structural and functional AIS proteins. Consistently, after blocking mDia1 activity, the action potential is affected, as well as, axonal polarity maintenance. These effects are due to the deficiency of AIS structural stability and alterations in axonal protein traffic, which can be compensated through expression or modulation of microtubules and microfilaments regulators. Taken together, our results indicate a new AIS regulator involved in AIS formation, maintenance and plasticity, which provides new insights on AIS regulation mechanisms. Further experiments will be necessary to completely understand mDia1 regulation at the AIS, and its implications in brain activity related diseases
DescriptionMemoria de Tesis doctoral presentada por Wei Zhang, para obtener el doctorado (Mención en Biología y Biomedicina ) por la Universidad Autónoma de Madrid (UAM), realizada bajo la dirección de Dr. Juan José Garrido Jurado.-- 176 pages
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