Date of Award

2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Peter B. Crino

Abstract

Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disorder that results form mutations in the TSC1 or TSC2 genes. TSC is a multisystem hamartoma syndrome with manifestations in the brain, heart, lungs, kidney, skin and eyes. Neurologically, TSC patients may exhibit severe epilepsy, cognitive disabilities, and autism spectrum disorders. TSC1 and TSC2 proteins form a heterodimeric complex that serves to inhibit mammalian target of rapamycin (mTOR) signaling pathway. TSC1 and TSC2 receive activating or inhibitory signaling from multiple inputs including growth factors, insulin signaling, energy and amino acid levels, and proinflammatory pathways, and then integrate those signals to regulate the activity of mTOR. mTOR signaling plays a critical role in regulating cell growth, transcription, translation, and autophagy. Animal models have shed light on certain features of TSC, but failed to recapitulate the disease completely and currently further research is under way to better understand this devastating disorder. To date, mTOR signaling hyperactivation has been demonstrated in TSC tubers at postnatal time points, thus we set out to study the profile of mTOR activation in the fetal brain. We utilized both mouse neural progenitors in vitro and developing brain in vivo systems to understand the effects of Tsc1 and Tsc2 during brain development. Furthermore, after the identification of a new mTOR regulatory protein Deptor (DEPDC6 gene), which inhibits the mTORC1 and mTORC2 signaling pathways similar to TSC1-TSC protein complex, we examined its role in brain development. We found that Deptor shRNA knockdown results in mTORC1 and mTORC2 activation in vitro as well as abnormal migration in vivo. Our results show that mTOR signaling pathway could be the common pathway on which TSC1, TSC2, and DEPTOR converge and exert their effects on brain development. These results suggest mTOR signaling and its downstream effectors could be targets for therapeutic treatment during embryogenesis and could potentially prevent abnormal brain development.

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