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Title: Functional characterisation of MYT1L, a brain-specific transcriptional regulator
Author: Kepa, Agnieszka Maria
ISNI:       0000 0004 5368 1831
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2014
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Abnormalities in brain development and maladaptive plasticity are thought to underlay a range of neurodevelopmental and neurological disabilities and disorders, such as autism spectrum disorders, schizophrenia and learning disability. Though many transcription factors are known to control important diverse aspects of embryonic development, the molecular mechanisms by which these factors coordinate processes such as neuronal differentiation remain unclear. Thus, there is a need to identify genes and pathways involved in these processes. Myelin transcription factor 1- like (MYT1L) has a property to convert fibroblast to neurons and it is specifically expressed in the brain. Since the fundamental steps in neural development and MYT1L gene are highly conserved in vertebrates, we anticipated that interference with its function may result in obvious phenotypes. To understand the role of MYT1L in the vertebrate development, we first examined its expression patterns in the zebrafish and mouse. We reported myt1l first manifestation in the telencephalon region around 24h post-fertilisation and gradual increase of its mRNA levels during fish embryogenesis. We have also examined mRNA levels of this gene in mouse brain and found Myt1l most prominent role just before birth, when neural development is most active. To investigate the role of MYT1L during neural differentiation we used lentiviral-mediated gene silencing of this transcription factor in human neural stem cells. Subsequent microarray analyses revealed a list of potential targets of MYT1L, most of which were down-regulated upon MYT1L silencing, suggesting that the expression of those genes is mediated by MYT1L. The analyses of gene expression patterns during stem cells development have revealed that Myocyte Enhancer factor 2 (MEF2A)-specific binding site is present in most of genes co-expressed with MYT1L. We hypothesised, that MEF2A may regulate the expression of MYT1L and MYT1L co-expressed genes. By examining the consequences of MEF2A down-regulation in neuronal stem cells we discovered that MYT1L expression was negatively regulated upon MEF2A silencing. Differential gene expression analyses revealed that the majority of genes deregulated upon knock-down of MEF2A were also de-regulated by knock-down of MYT1L, suggesting that both genes operate through similar or possibly the same regulatory pathways. Therefore, the findings presented throughout this thesis contribute towards a better understanding of MYT1L role, function and its molecular mechanisms involved in the neural development. Further work is required to provide a greater understanding of MYT1L involvement in normal brain growth and maturation and the collective results might help to unravel molecular mechanisms underlying neurodevelopmental disorders and possibly help in identifying new therapeutic targets.
Supervisor: Desrivieres, Sylvane ; Schumann, Gunter Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available