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Title: The expression and regulation of lama1, a gene encoding Laminin alpha 1, during zebrafish development
Author: Pickering, Joseph
ISNI:       0000 0004 2735 8088
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2012
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The Hedgehog (Hh) signalling pathway is one of the major signalling pathways governing embryonic and adult development in bilateria, yet many of the direct targets of Hh signalling remain unknown. Here, I use the zebrafish embryo to investigate two potential Hh target genes that were identified in the mouse. These are lama1, encoding Laminin α1, and c125, a novel gene hypothesised to play a role in motor neuron development. Laminins are conserved heterotrimeric glycoproteins, of which there are at least 16 different isoforms, generated from Laminin α, β, and γ subunits. Laminins are an essential component of basement membranes (BMs), which are specialised forms of the extra-cellular matrix (ECM) crucial for normal patterning, proliferation, migration, and differentiation of many different cell types. Mutations in lama1 cause embryonic lethality in mouse and zebrafish, demonstrating that Laminin α1 function is critical for embryonic development. The aims of this study were to assess the expression of lama1 and c125 during zebrafish embryonic development, and to explore a possible role for Shh in their regulation. I also aimed to determine the regulatory sequences controlling lama1 expression using a bacterial artificial chromosome (BAC) transgenic zebrafish approach. My data reveal that the enhancer elements controlling zebrafish lama1 expression are located within intron 1 of lama1. Within this intron, I have uncoupled the enhancers that regulate lama1 expression in the muscle fibres, from enhancers that regulate lama1 expression in the anterior CNS, neural tube, and the eye. These findings are of particular importance because ectopic expression of lama1 in mouse models of congenital muscular dystrophy restores normal muscle function. Therefore, the characterisation of lama1 regulation provides a framework for future studies to identify drugs stimulating endogenous lama1 expression in dystrophic muscles.
Supervisor: Borycki, Anne-Gaelle Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available