Molecular and phenotypic characterisation of zebrafish mutants displaying defects in axonal development in the central nervous system

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Molecular and phenotypic characterisation of zebrafish mutants displaying defects in axonal development in the central nervous system

Mangoli, Maryam; (2004) Molecular and phenotypic characterisation of zebrafish mutants displaying defects in axonal development in the central nervous system. Doctoral thesis (Ph.D.), University College London (United Kingdom). Green open access

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Abstract

Zebrafish mutants isolated from large-scale chemical mutagenesis screens display defects in various aspects of embryonic development (Driever, 1996; Haffter, 1996). The aim of this project was to investigate the role of monorailtv53a , eisspaltety77e, otterta76b and shrinkU41 in central nervous system (CNS) development, both by characterisation of mutant phenotypes and by genetic mapping and identification of the mutated genes. It was anticipated that the findings would provide new insights into early vertebrate brain development by increasing knowledge of the components involved in neuronal patterning and axon pathfinding in the CNS. Phenotypic analysis of homozygous monorailtv53a mutant embryos revealed a reduction in the width of the floor plate in the ventral CNS as well as defects in induction and patterning of adjacent neurons in the midbrain and hindbrain. The gene was mapped to linkage group 17 in a region harbouring two fork head genes, foxA1 and foxA2, both of which are expressed in the floor plate. Sequence analysis of foxA1 revealed no significant changes in amino acid sequence between monorail and wild-type siblings. Sequence analysis of foxA2 identified a nonsense mutation in the conserved fork head DNA binding domain in monorail. This change creates a stop codon and results in absence of 84 % of the DNA binding domain, complete loss of transactivating domains II and III and is predicted to render the FoxA2 protein nonfunctional. Phenotypic characterisation and genetic mapping of shrinkU41, otterta76b and eisspaltety77e was undertaken and revealed defasciculation of forebrain commissural axons and abnormal retinotectal projections in all mutants. These genes were mapped to linkage groups 6 (shrink) and 14 (otter and eisspalte). Further investigation of possible candidates for the shrink, otter and eisspalte phenotypes is underway.

Type:	Thesis (Doctoral)
Qualification:	Ph.D.
Title:	Molecular and phenotypic characterisation of zebrafish mutants displaying defects in axonal development in the central nervous system
Open access status:	An open access version is available from UCL Discovery
Language:	English
Additional information:	Thesis digitised by ProQuest.
Keywords:	(UMI)AAIU643934; Biological sciences; Health and environmental sciences; Axon development
URI:	https://discovery.ucl.ac.uk/id/eprint/10104155