Roles of Class II Histone Deacetylases in Muscle and Brain
| dc.contributor.advisor | Olson, Eric N. | en |
| dc.creator | Kim, Mi-Sung | en |
| dc.date.accessioned | 2011-09-30T18:54:04Z | |
| dc.date.available | 2012-12-01T18:54:04Z | |
| dc.date.issued | 2010-01-12 | |
| dc.description.abstract | A defining feature of brain and muscle is their ability to remodel their phenotypes in response to extracellular stimuli to maintain the balance between physiological demand and functional capacity. Successful adaptation to the environment is essential for the survival and this plasticity is achieved by activation of intracellular signaling pathways and subsequent activation of gene expression, the so-called “extrinsic genetic programs”. Although it has been well known that calcium-dependent signaling is critical to regulate this extrinsic genetic program, little is known about how calcium-dependent signaling is propagated to the nucleus to induce the transcription of specific genes responsible for tissue plasticity. Furthermore, physiological and behavioral consequences of failure of plasticity are still poorly known. Here, I demonstrate that class II HDACs and MEF2 transcription factors are essential for tissue plasticity, and that defects of this signaling pathway in muscle and brain cause muscle-fatigue susceptibility and a pronounced neurological deficit. Protein kinase D1, a potent class II HDAC kinase, in skeletal muscle promotes transformation to type I myofibers through activation of MEF2. Conversely, genetic deletion of PKD1 in type I myofibers increases susceptibility to fatigue, suggesting that PKD1 is a key regulator of skeletal muscle plasticity. Deletion of the class II HDAC4 in neurons impairs memory formation and synaptic plasticity in mice, while mice lacking class II HDAC5 exhibit normal memory formation. Furthermore, deletion of both HDAC4 and HDAC5 in neurons produced a more pronounced neurological deficit, including severe seizure activity, suggesting distinct and redundant roles for HDAC4 and HDAC5 in memory formation and in brain homeostasis. While deletion of MEF2C in brain causes impairments in memory formation, mice lacking MEF2A and MEF2D exhibit no such deficits. Furthermore, deletion of MEF2A, MEF2C, and MEF2D results in decreased REM sleep, brief spontaneous seizures, and postnatal lethality accompanied by increased apoptosis, suggesting distinct and redundant roles for MEF2A, MEF2C, and MEF2D in brain homeostasis. Taken together, these series of studies provide important clues to understanding the mechanism by which extrinsic genetic programs are regulated in vivo, especially focusing on the regulation of muscle and brain functions. | en |
| dc.identifier.oclc | 761089784 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/906 | |
| dc.language.iso | en | en |
| dc.subject | Memory | en |
| dc.subject | Myogenic Regulatory Factors | en |
| dc.subject | Synapses | en |
| dc.title | Roles of Class II Histone Deacetylases in Muscle and Brain | en |
| dc.type | Thesis | en |
| dc.type.material | Text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Genetics and Development | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |
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