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Petricca, Stefania (2015): Transcription factor Pax6 regulates cell cycle progression and cell fate determination: the modular logic of complex transcriptional control. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)



The development of the central nervous system relies on the tight regulation of the neural progenitor proliferation and differentiation in order to generate new neurons. The transcription factor Pax6 coordinates these functions during the development of the mammalian forebrain, using the paired DNA binding domain. This is a bipartite DNA-binding domain constituted by two subdomains, the PAI and the RED, binding the DNA in a cooperative or independent manner in order to control specific targets. Focusing on the activity of Pax6 as regulator of cell proliferation and of cell fate determination, I aimed to understanding how these functions are regulated at the molecular level, using the developing ventral forebrain as a model. In this work the role of the RED domain of Pax6 as a regulator of cell cycle progression is investigated. The mutation of the RED subdomain leads to an increase of progenitors in active mitosis (phospho-histone3 positive cells) in the ventral telencephalon at midneurogenesis. Similar result was obtained in the progenitors of the dorsal telencephalon. The increment in the phospho-histone3 positive cells is followed by the increase in cell death in both dorsal and ventral forebrain. These evidences suggest impairments in the cell cycle progression of the progenitor cells in the RED domain mutant. The importance of full activity of the RED domain of Pax6 for the proper progression of the cell cytokinesis is shown via ex-vivo live imaging, performed on ventral developing forebrain of Pax6Leca2 mutant animals (RED domain mutant). To elucidate the molecular mechanisms underlying the observed phenotype, transcriptome of the Pax6Leca2 mutants and their age matching siblings is analyzed, identifying a potential candidate gene: the Holliday junction recognition protein (HJURP). The overexpression of the HJURP protein in the wild type progenitors in vitro resembles the impairment of cytokinesis observed in Pax6Leca2 mutant. In summary, my data suggest new mechanisms for the regulation of cytokinesis in progenitors mediated by the RED domain of Pax6 and indicate that the full functionality of the paired domain is a prerequisite for Pax6 to function as fate determinant.