Date of Graduation
8-2014
Document Type
Dissertation (PhD)
Program Affiliation
Biomedical Sciences
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Seonhee Kim, Ph.D.
Committee Member
Ju-Seog Lee, Ph.D.
Committee Member
Pierre D. McCrea, Ph.D.
Committee Member
Jeffrey A. Frost, Ph.D.
Committee Member
Eric C. Swindell, Ph.D.
Abstract
Through their biased localization and function within the cell, polarity complex proteins are necessary to establish the cellular asymmetry required for tissue organization. Well-characterized germinal zones, mitogenic signals, and cell types make the cerebellum and neocortex excellent models to address the critical function of polarity complex proteins in the generation and organization of neural tissues. Here we report a focal distribution of Pals1, a central component of the apical complex, in progenitors. Our genetic analyses revealed that Pals1 deletion in the brain developed a remarkably undersized and disrupted layer structure of cerebral cortex and cerebellum. Furthermore we demonstrated that Pals1 is not only essential for brain organogenesis, but is also required for maintaining a cycling pool of progenitors in germinal zones and preventing premature differentiation. Interestingly, we did not detect profound changes in the downstream effects of well-established mitogenic/morphogenetic signaling through Shh and Notch in the Pals1 mutant. However, the localization of other apical complex proteins and tight junction proteins was severely affected by the absence of Pals1, which likely resulted in impaired cell adhesion and compromised tissue integrity. Importantly, we have found a critical function of Pals1 in regulating mitosis as Pals1 deletion causes the delay of mitotic progression and incomplete chromosome segregation. Additionally, we uncovered a crucial downstream factor mediating Pals1 function, Pttg1, which is known as an essential protein for sister chromatid segregation during mitosis. Thus, our study identifies Pals1 as a new intrinsic factor required for the proliferation and differentiation of neural progenitor cells by ensuring normal progression of mitosis.
Keywords
cell polarity, progenitor, neocortex, cerebellum, junction, adhesion, development, shh signaling