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Authors: Tetruashvily, Mazell
Advisors: Boulanger, Lisa M
Contributors: Molecular Biology Department
Keywords: aging
Synapse elimination
Subjects: Neurosciences
Molecular biology
Issue Date: 2015
Publisher: Princeton, NJ : Princeton University
Abstract: The mammalian neuromuscular junction (NMJ) undergoes prominent developmental synapse elimination, during which supernumerary motor neuron axons are retracted to produce mature patterns of connectivity. Despite the critical role of synapse elimination in the maturation of motor function, the molecular mediators of this process remain elusive. Specific immune proteins, members of the class I major histocompatibility complex (MHCI), regulate synapse elimination in the developing mammalian visual system, and are highly expressed in adult motor neurons. MHCI is also expressed during synapse elimination at the developing NMJ. Building on preliminary data from the Boulanger lab that synapse elimination at the NMJ is impaired in mice genetically lacking cell-surface expression of most MHCI proteins (β2m-/-TAP-/- mice), this thesis will demonstrate that classical and nonclassical MHCIs are critical for promoting developmental synapse elimination at the NMJ. In broadly MHCI-deficient mice as well as transgenic mice lacking only classical MHCIs (Kb-/-Db-/- mice), significantly more motor end plates remain multiply-innervated relative to WT at postnatal day 15 (P15), when synapse elimination is normally complete. Multiply-innervated NMJs are still apparent in MHCI-deficient adults (P29-60) and aged animals (P365), suggesting that loss of MHCI persistently disrupts synapse elimination at the NMJ. Studies in transgenic mice over-expressing of MHCI H-2Db show accelerated synapse elimination indicating that normal synapse elimination can be bi-directionally modulated by MHCI: decreasing MHCI levels disrupts synapse elimination, while increased MHCI levels accelerate synapse elimination. The thesis also identifies some of the dozens of classical and/or nonclassical MHCIs that are involved in synapse elimination at the NMJ. Profiling the expression of specific MHCI genes at the NMJ before, during, and after synapse elimination has generated a developmental comparison of classical and nonclassical MHCI expression profiles in three muscle groups. These results will allow a better understanding of the molecular mechanism by which MHCI regulates synapse elimination. Finally, this thesis explores a role for MHCI in aging-related synapse loss. MHCI is up-regulated at the NMJ during aging-related denervation. This pathological synapse loss is ameliorated in MHCI-deficient animals suggesting an aberrant reactivation of MHCI-guided developmental synapse elimination in aged animals.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Molecular Biology

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