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dc.contributor.advisorBonni, Azad
dc.contributor.authorMejia, Luis Antonio
dc.date.accessioned2013-10-18T13:03:44Z
dash.embargo.terms2014-10-10en_US
dc.date.issued2013-10-18
dc.date.submitted2013
dc.identifier.citationMejia, Luis Antonio. 2013. Interaction Proteomics of Autism Spectrum Disorder- and Intellectual Disability-Associated Proteins Identifies a Novel Hap1-Tsc1 Signaling Link that Controls Neuronal mTORC1 Signaling and Pyramidal Neuron Morphogenesis. Doctoral dissertation, Harvard University.en_US
dc.identifier.otherhttp://dissertations.umi.com/gsas.harvard:11190en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11181106
dc.description.abstractAutism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental disorders of cognition that remain incompletely understood. Here, using a computation-assisted interaction proteomics approach in neural cells including primary neurons, we isolate high-confidence binding partners of proteins linked to ASD and ID. As part of these studies, we uncover the brain-enriched, coiled-coil domain protein huntingtin-associated protein 1 (Hap1) as a novel functional binding partner of the tuberous sclerosis complex (TSC) protein Tsc1. We validate and map the Hap1-Tsc1 interaction, and find that Hap1 and Tsc1 form a complex endogenously in the brain. Hap1 knockdown in primary hippocampal neurons triggers the specification of supernumerary axons, and in utero knockdown of Hap1 in mice profoundly impairs the positioning of pyramidal neurons in the hippocampus in vivo. Importantly, the Hap1 knockdown-induced phenotypes in primary neurons and in vivo recapitulate the phenotypes induced by Tsc1 knockdown. We also define a mechanism by which Hap1 regulates Tsc1 function. We observed that exogenous Hap1 promotes the abundance of soluble, stable Tsc1 expressed in cells. Hap1 knockdown in neurons reduces Tsc1 abundance and accordingly stimulates the activity of mTORC1, as reflected by phosphorylation of the ribosomal protein S6. Importantly, inhibition of mTORC1 signaling suppresses the Hap1 knockdown-induced axon phenotype in hippocampal neurons. Collectively, these findings define a novel relationship between Hap1 and Tsc1 that regulates neuronal Tsc1 abundance, pyramidal neuron development, and neuronal mTORC1 signaling, with important mechanistic implications for our understanding of neurodevelopmental disorders of cognition.en_US
dc.language.isoen_USen_US
dash.licenseMETA_ONLY
dc.subjectNeurosciencesen_US
dc.titleInteraction Proteomics of Autism Spectrum Disorder- and Intellectual Disability-Associated Proteins Identifies a Novel Hap1-Tsc1 Signaling Link that Controls Neuronal mTORC1 Signaling and Pyramidal Neuron Morphogenesisen_US
dc.typeThesis or Dissertationen_US
dash.depositing.authorMejia, Luis Antonio
dash.embargo.until10000-01-01
thesis.degree.date2013en_US
thesis.degree.disciplineBiology: Medical Sciences, Division ofen_US
thesis.degree.grantorHarvard Universityen_US
thesis.degree.leveldoctoralen_US
thesis.degree.namePh.D.en_US
dc.contributor.committeeMemberBlenis, Johnen_US
dc.contributor.committeeMemberSahin, Mustafaen_US
dc.contributor.committeeMemberKaeser, Pascalen_US
dc.contributor.committeeMemberGill, Graceen_US
dash.contributor.affiliatedMejia, Luis Antonio


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