The regulation of RNA Polymerase I-mediated transcription in forebrain neurons

THE REGULATION OF RNA POLYMERASE I-MEDIATED TRANSCRIPTION IN FOREBRAIN NEURONS Scott Carl Smith November 29,2011 Ribosomal biogenesis failure may contribute to neurodegenerative diseases, while its excessive activation has been shown to drive tumor growth. As ribosomal production is initiated and regulated by the Poll-mediated transcription of rRNA genes in the nucleolus, the latter process had the attention of most researchers interested in the dysregulation of ribosomal biogenesis in disease. When this work began, regulation of Poll-mediated transcription in neurons had been poorly characterized. The goal of this research has been to better define factors and signaling pathways that regulate neuronal Poll activity. The first hypothesis tested was that DNA damage induced by a DNA topoisomerase poison, etoposide, blocks neuronal Poll. Intracarotid delivery of etoposide to adult rats resulted in Poll inhibition in the neocortex; however no apoptosis was found. In neonate rats that received intracerebroventricular injections of etoposide we observed inhibition of Poll in neurons in the neocortex and hippocampus. Neuronal apoptosis was observed in these brain structures following etoposide treatment. Therefore, these results confirm that neuronal Poll is sensitive to etoposide-induced DNA damage and that such a sensitivity is present in both young and mature neurons of whole rats. These results also demonstrate that Poll inhibition is distinct from the