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Neurogenesis Defects and Tumorigenesis in BCCIP Deficient Mice

by
Yi-Yuan Huang
M.S., National Yang-Ming University, Taipei, Taiwan - 2004

Thesis Advisors: Zhiyuan Shen M.D., Ph. D.
Graduate Program Cellular & Molecular Pharmacology


CINJ - Auditorium A
New Brunswick

Thursday, January 19, 2012
1:00 p.m.


Abstract

Multiple DNA repair pathways are involved in the orderly development of neural systems at distinct stages. The homologous recombination pathway is required to resolve stalled replication forks and critical for the proliferation of progenitor cells during development. HR is also critical to ensure high fidelity of DNA replication and maintenance of genomic integrity. Thus, defective HR is associated with both impaired neurogenesis and tumorigenesis, but the relationship between the two outcomes has been elusive. BCCIP is a BRCA2 and CDKN1A interacting protein implicated in HR and multiple processes related to the maintenance of genomic stability. In this study, we determined the role of BCCIP in neural development and tumorigenesis using a conditional BCCIP knock-down mouse model. BCCIP deficiency caused extensive spontaneous DNA damage and cell death in the proliferative cells, and impaired neural progenitorís self- renewal capability. This significantly affected embryonic and postnatal neural development, causing severe ataxia, cerebral and cerebellar defects, and microcephaly. Neurogenesis defects can be rescued by concomitant deletion of p53 gene, but this leads to rapid formation of medulloblastoma with recurrent chromosomal alterations, including activation of the Sonic hedgehog (SHH) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. We also observed higher expression level of Math1, N-myc, cyclin D1 and cyclin D2. Interestingly, recovery of BCCIP protein expression occured in all medulloblastomas. Thus, early in tumorigenesis (initiation), BCCIP has function in DNA repair and can act as a tumor suppressor. However, during tumor progression, BCCIP may be required for tumor growth due to its role supporting cell proliferation. In summary, our study suggests that BCCIP has a key role in neural development by maintaining an orderly proliferation of neural progenitors, and tumorigenesis can occur when impaired tissue development is circumvented without safeguarding genomic integrity.


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