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Title: The regulatory logic of Pax3 expression in the neural tube
Author: Moore, S. J.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2012
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The development of complex tissues is dependent on the specification and maintenance of distinct transcriptional identities within populations of equivalent progenitors. In the vertebrate neural tube, progenitor identity is specified by the spatially organised expression of transcription factors within the dorso-ventral (DV) axis of the tissue. A series of selective cross-repressive interactions between transcription factors expressed in adjacent domains forms the basis of a gene regulatory network (GRN), which acts to define and maintain the boundaries between progenitor populations. Pax3 is a key member of the neural tube GRN that is transcribed throughout the dorsal domains of the spinal cord and exhibits a ventral boundary of expression at the level of the sulcus limitans. The regulatory mechanisms that induce Pax3 transcription in neural progenitors and subsequently produce a sharp ventral boundary of gene expression are poorly understood. Using a genetic lineage tracing strategy in mice, we show that the position of the Pax3 expression domain is established within the neural plate and subsequently maintained throughout spinal cord development. Additionally, we demonstrate that V0 interneuron progenitors transiently express Pax3 during their early development. We employ a comparative genomics based approach to investigate the molecular basis of Pax3 transcription, revealing several novel enhancers associated with the locus. Functional dissection of an early central nervous system (CNS) specific enhancer supports the role of the Wnt signaling pathway in the induction of Pax3 transcription. Furthermore, we establish the function of direct transcriptional repression in the establishment of the Pax3 expression domain. Analysis of a second CNS specific enhancer reveals that Pax3 expression is dependent on autoregulation and Pax7 mediated positive feedback post-neurulation. Together, these data indicate that the temporal activity of two distinct enhancers underlies the regulatory logic of Pax3 expression in the neural tube.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available