| Summary: | The diversification of cellular subtype during development is directed by combinatorially acting transcription factors and signaling pathways that act to regulate subtype specific gene expression profiles in post-mitotic cells. These key transcription factors and signaling pathways operate in a transcriptional network, which act to establish cellular subtype identity over the course of a developing cellular lineage. Lineage progression towards ever increasing cellular diversity is often viewed as a ratchet mechanism of irreversible steps resulting in the specification and then terminal differentiation of cell subtype identities. From this viewpoint, terminally differentiated cells have long been considered as irreversibly locked into their identity. In a landmark article, Blau and Baltimore (Blau and Baltimore, 1991) postulated that a cell’s identity, or differentiated status, requires persistent active regulation, rather than lapsing into a passive ‘locked-in’ state. While little genetic evidence was available at the time, sufficient evidence has since accumulated to propose that the terminally differentiated state, or identity, of a cell subtype indeed requires active maintenance. Currently, however, we have only the most rudimentary understanding of the regulatory mechanisms that maintain neuronal identity. This thesis presents a systematic effort to characterize the role of the transcriptional networks that differentiate neuronal identity in the mature neurons of the adult nervous system. Using the Drosophila Tv cluster neurons I show the persistent requirement of 1) target derived signals and 2) networks of transcription factors for the maintenance of the cellular subtype specific expression profiles of terminal differentiation genes, genes that define these neuron’s function and identity. This work establishes one of the most comprehensive transcriptional models for maintenance of cell identity to date. It also provides novel mechanistic insights showing that cellular differentiation is a persistent process that requires active maintenance, rather than being passively ‘locked-in’ or unalterable. As such, the work of this thesis provides critical insight that provides a strong foundation for further efforts to determine how neuronal identity is maintained. === Medicine, Faculty of === Graduate
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