Role of Dmrt5 during development of midbrain dopaminergic progenitors

• Main Author: Farley, Emma Kirsten
• Other Authors: Li, Meng ; Gale, Emily
• Published: Imperial College London 2011
• Subjects: 611
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.542567

This thesis investigates the previously un-described role of Dmrt5, a zinc-finger transcription factor, in ventral midbrain development. The spatio-temporal expression pattern of Dmrt5, described for the first time in this thesis, suggests that Dmrt5 may have a role in midbrain dopaminergic development. Exogenous expression of Dmrt5, by in ovo electroporation in the chick embryo and over expression during neuronal differentiation of mouse epistem cells, causes ectopic expression of Hes1, a gene involved in the timing of neurogenesis. Dmrt5 ectopic expression also reduces the number of cells undergoing proliferation and inhibits terminal differentiation. These findings are consistent with the previously described phenotype observed upon Hes1 over expression. Studies in neuronal progenitors derived from mouse epistem cells indicate Dmrt5 mediates this effect by binding to the Hes1 promoter region. Genome-wide analysis of Dmrt5 over expression within the developing chick embryo, implicate Dmrt5 in specification of dorsal-ventral patterning. Dmrt5 promotes a floor-plate-like transcriptional profile when it is ectopically expressed in the dorsal ventral lateral midbrain. This observation is confirmed by ectopic expression studies in the developing chick and by over expression studies in neural progenitors differentiated from mouse epistem cells. In conclusion the data presented in this thesis describe the role of Dmrt5 in neurogenesis and dorsal-ventral patterning of the ventral midbrain. This data contributes to our knowledge of the developmental program involved in the creation of midbrain dopaminergic progenitors.