Date of Award

9-29-2010

Document Type

Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Laura Ment

Abstract

Investigating Hypomyelination And Axon Guidance Defects In Tuberous Sclerosis Complex. Hasani Baharanyi, Duyu Nie, and Mustafa Sahin, Department of Neurology, Childrens Hospital of Boston, Harvard Medical School, Boston, MA. (Sponsored by Laura Ment, Department of Pediatric Neurology, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT. Hypomyelination and neuronal networking defects are noted characteristics of Tuberous Sclerosis Complex. We investigated how the TSC1/2 complex contributes to both of these processes. Given recent evidence describing the contribution of NRG/ErbB receptor pathway in myelination, we hypothesized that CNS hypomyelination is due to reduced expression of the Neuregulin-1/ErbB receptor pathway components. We measured neuronal expression of NRG1, ErbB2, ErbB3, and ErbB4 mRNA, protein, and cDNA levels. Surprisingly we found that expression of NRG1 and ErbB3 is unaffected in TSC deficient neurons (P=0.2718 and 0.1418 respectively). Neuronal expression of ErbB2 and ErbB4 in TSC-deficient neurons depended on the modality used to quantify expression. To investigate neuronal miswiring in Tuberous Sclerosis Complex, we focused on the barrel cortex, which depends on the repulsive effects of the ephrin/Eph pathway for its formation. Previous data from our laboratory suggest that the TSC1/2 complex regulates these repulsive effects. We stained the barrel cortices of mice with both cytochrome oxidase to examine qualitative differences between wild-type, Tsc2+/-, and Syn-Cre;Tsc1flox/flox mice. Tsc2+/- mice had normal barrel cortices. There was no cytochrome oxidase staining in the conditional knockout mice.

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