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Specific roles of laminins during vertebrate embryogenesis

Pollard, Steven Michael; (2002) Specific roles of laminins during vertebrate embryogenesis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The notochord is critical for the normal development of vertebrate embryos. Zebrafish mutants, bashful (bal), grumpy (gup) and sleepy (sly) were identified in mutagenesis screens and have defects in notochord differentiation. By positional cloning I identified lama1, encoding Laminin α1, as a candidate for the bal gene. Analysis of mRNA expression, antisense knockdown and sequencing of the mutant lama1, confirmed that mutations in this gene are responsible for the bal phenotype. A similar approach was taken to identify the gup gene. Meiotic mapping identified a region containing lamb1, encoding Laminin β1. Cloning and sequencing of lamb1 from mutants revealed a non-sense mutation. These results identify a role for Laminin αl and Laminin β1 in notochord differentiation. Concurrent work in our laboratory revealed that the third mutant, sly, encodes the Laminin γl chain (Parsons et al., 2002). Thus, the laminin 1 isoform, a heterotrimer comprising the α1β1γ1 chains, is necessary for notochord differentiation. bal mutants differ from gup and sly, as failure of notochord differentiation is not as extensive, occurring only in anterior regions. We hypothesised this was due to a redundant role of another a chain. Characterisation of lama4 and lama5, encoding Laminin α4 and α5 chains, respectively, showed that both control aspects of notochord differentiation. Furthermore, lama5 has a functionally redundant role with lama1 during CNS development. Characterisation of lama2 identifies a role for Laminin α2 chain in muscle function, consistent with loss-of-function phenotypes in human and mouse. Hence, I demonstrate different roles for specific laminin chains during zebrafish development, confirming and extending results from studies in other vertebrate systems. Finally, I studied integrin α6, integrin β4, and integrin-linked kinase (ILK), to determine their role during development. The results suggest these genes control cell movements during gastrulation, rather than notochord differentiation.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Specific roles of laminins during vertebrate embryogenesis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Health and environmental sciences; Embryogenesis
URI: https://discovery.ucl.ac.uk/id/eprint/10101133
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