During embryonic development, the Hedgehog (Hh) signaling pathway plays an
important role in the growth and patterning of numerous tissues and organs. In the
developing retina, Hh signaling regulates the proliferation and differentiation of retinal
progenitor cells (RPC) through mechanisms that are not completely understood. The
principal downstream mediators of the Hh pathway are the Gli transcription factors (Gli1-3),
which regulate the expression of target genes responsible for the effects of the Hh pathway
on RPC. The network of genes targeted by this pathway in neural progenitor cells however,
remains unknown. The objective of this thesis was to identify and characterize novel targets
of Hh/Gli during retinal development. Using a computation approach, 390 genes were
identified as having at least one conserved Gli binding motif within the vicinity of the coding
sequence between humans and mice. During validation, I demonstrate that 30 of 46 selected
targets were modulated in response to Hh pathway activation in either E14.5 and/or P0.5
retinal explants and that the induction of 25 of these were significantly different between the
two developmental stages. Included in this list of Hh-modulated genes were Sox8 and Ndp,
two highly inducible genes that are direct targets of Gli2. Functionally, I was unable to
determine a role for Sox8 during retinal development which could reflect compensation by
the closely related Sox9 and Sox10 genes. Ndp on the other hand was found to be sufficient
and required for Hh mediated induction in progenitor cell proliferation and cell fate
determination. Therefore, in this thesis Hh target genes have been identified which could
provide some insight into the mechanisms that are responsible for the cellular outcome of a
response to the pathway.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OOU-OLD./22655 |
| Date | 19 March 2012 |
| Creators | McNeill, Brian |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
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