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Dakim K. Gaines
B.A., St. Mary`s College of Maryland-2009
Thesis Advisor: Zhiyuan Shen M.D., Ph.D.
Graduate Program in Cellular & Molecular Pharmacology
Cancer Institute of New Jersey (CINJ)
Friday, April 15, 2016
The DNA damage response network is intimately linked to neural development and tumorigenesis. Various DNA repair pathways play distinct roles at different stages of neural development. BCCIP (BRCA2 and CDKN1A interacting protein) is implicated in preventing DNA replication stress by supporting homologous recombination. Our lab has previously shown that using a GFAP-Cre driven cre/lox system, that Bccip knockdown mice display multiple neurodevelopmental defects including ataxia, microcephaly, and growth retardation. However these defects are present during the perinatal period and the animals have a normal life expectancy. To understand the effects of a permanent deletion, we have developed a GFAP-Cre driven conditional Bccip knockout mouse (BCKO). BCKO mice displayed severe and permanent microcephaly, growth retardation and ataxia. We found that BCKO mice had reduced progenitor cell population and lower layer neuron depletion, but there is little effect on upper layer neurons. Secondly this study examined the roles Bccip play in gliomagenesis. Several previous studies have suggested that Bccip has tumor suppression functions in multiple tumor types and our lab has shown that the depletion of Bccip and concomitant removal of p53 in the brain early during neurodevelopment leads to the rapid development of medulloblastomas. Therefore we hypothesized that depleting Bccip and removing p53 in adult mice may promote gliomagenesis. We created brain-specific conditional Bccip knockdown and knockout mouse models driven by a tamoxifen inducible Nestin-creERT2. Using an inducible Cre system gave us temporal control over Cre activity to target specific cell populations upon tamoxifen exposure. When a Bccip knockout was induced by tamoxifen at 6 weeks of age, we did not observe an increased risk for glioma formation in the Nestin -Cre-ERT2+/-: Bccip-/- (Bccip conditional knockout) mice. However, these mice had a worse overall survival when compared to un-induced mice. Interestingly this phentoype was partially rescued by a conditional p53 deletion suggesting that Bccip plays an important role in the survival of adult mice. It will be interesting to determine if inducting a Bccip knockout at different ages with the combination of p53 inactivation would promote gliomagenesis in future studies.