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Xin Tong
Master of Science, Wuhan University - 2004

Thesis Advisor: Chih-Cheng Tsai, Ph.D.
Graduate Program in Physiology & Integrated Biology

Conference Room 258
School of Public Health

Wednesday, February 16, 2011
2:00 p.m.


Ataxin-1 (ATXN1) and Brother of Ataxin-1 (BOAT) are two homologous transcriptional co-repressors involved in the pathogenesis of Spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disorder. While the detailed function of these proteins remains unclear, recent evidence has suggested the involvement of ATXN1 and BOAT in transcriptional repression. Particularly, both proteins bind the conserved transcriptional co-repressor SMRT-family (silencing mediator of retinoic acid and thyroid hormone receptors) proteins and HDAC3. SMRT-family proteins are well-known co-repressors which are involved in multiple pathways, and as such, the goal of this thesis is to further decipher the specific pathways in which both ATXN1 and BOAT are involved.
Employing a combination of Drosophila and mammalian cultured cell systems, my studies reveal that both ATXN1 and BOAT are components in the Notch pathway. Both ATXN1 and BOAT are direct interacting factors of CBF1, the central transcription factor in the Notch signaling pathway. Significantly, the association between ATXN1 or BOAT and CBF1 is disrupted when Notch is activated, suggesting that ATXN1 and BOAT are transcriptional co-repressors.
Moreover, I further discovered that the properties of ATXN1 and BOAT are not identical in the context of the Notch pathway. In flies, expressing BOAT, but not ATXN1, down-regulates a Notch target gene----E(spl)mÔ. In addition, I further characterized that the difference of ATXN1 and BOAT in the context of Notch signaling lies at the Su(H) level, the Drosophila homolog of CBF1. ATXN1 and BOAT respond differently to mutation of Su(H), possibly because a specific interaction takes place between BOAT and CtBP, another transcriptional co-repressor known to be involved in the Notch pathway. These results indicate that CtBP in part contributes to the functional differences between these two related factors.
Based on all the evidence obtained, I propose that both ATXN1 and BOAT play a role in the Notch signaling pathway as transcriptional co-repressors, but with different properties. This study contributes new ideas about the pathogenic mechanisms of SCA1, and hopefully will be implicated in the therapy of neurodegenerative diseases.

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