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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

The Chromatin Remodelling Contributions of Snf2l in Cerebellar Granule Neuron Differentiation

Goodwin, Laura Rose 01 October 2018 (has links)
Recent studies have uncovered de novo mutations of the gene encoding the chromatin remodelling protein Snf2l in patients with schizophrenia, Rett-like syndrome and intellectual disability. Snf2l and its closely related protein, Snf2h, play a critical role in embryonic and post-natal brain development. Murine models lacking functional Snf2h or Snf2l point to complementary activities of these remodelers; Snf2h cKO mice present with a significantly reduced cerebellum, while Snf2l Ex6DEL (exon 6 deleted) cerebella are larger than their wild-type counterparts. Granule neuron progenitors (GNPs) isolated from Ex6DEL cerebella display delayed cell cycle exit and hindered terminal differentiation compared to wild-type controls. Moreover, loss of Snf2l activity results in widespread transcriptome shifts which underlie the Ex6DEL GNP differentiation phenotype. In particular, key transcription factors are differentially expressed without Snf2l remodelling activity. We confirm that ERK pathway activation is misregulated in Ex6DEL GNPs, possibly in response to elevated fibroblast growth factor 8 (Fgf8) expression in these cultures. We find that Snf2l activity maintains the chromatin landscape throughout GNP differentiation, as Ex6DEL cultures have a global increase in chromatin accessibility. We suggest that Snf2l-mediated chromatin condensation is responsible for proper regulation of gene expression programs in GNP differentiation.
2

The Molecular Basis of Medulloblastoma: Interaction of Hedgehog and Notch Signalling in Brain Development and Cancer

Elaine Julian Unknown Date (has links)
Brain tumours comprise about 25% of all cancers in children. Medulloblastoma – which arise in the cerebellum – are the most common and severe malignant pediatric brain tumour and the leading cause of cancer-related deaths in children under the age of 9. Treatment of medulloblastoma remains conventional, with surgery followed by chemotherapy and radiation. These measures are successful in about 60-80% of cases but treatment results in severe side effects due to its toxicity to the central nervous system. Therefore it is of utmost importance to define the signalling pathways and genetic changes involved in the formation of medulloblastoma in order to allow for better diagnosis and treatments with higher efficiency and decreased toxicity. The cell of origin for medulloblastoma is thought to be the granule neuron progenitor, a cell type arising from cerebellar stem cells of the ventricular zone. After birth granule neuron progenitors differentiate into mature granule neurons which populate the majority of the cerebellum and are crucial for its cognitive functions and motor coordination. The Hedgehog signalling pathway plays an important role in medulloblastoma generation and murine models with activated Hedgehog signalling develop medulloblastoma at high frequencies. In addition, the Notch pathway has been implicated in the generation of medulloblastoma, and interaction between the two pathways has been suggested. Inhibitors of both Hedgehog and Notch are currently in clinical trials however knowledge of possible interactions between them could lead to more effective treatment strategies. The aim of this project was to investigate the interaction of Hedgehog and Notch signalling in normal brain development and medulloblastoma. Two mouse models allowed activation of Hedgehog and inactivation of Notch signalling in granule neuron progenitors and cerebellar ventricular zone stem cells. In granule neuron progenitors canonical Notch signalling is not required and the layering and cell types of RBP-Jlox/lox;Math1-Cre cerebella appear identical to control brains. In contrast, Notch inactivation in ventricular zone stem cells with GFAP-Cre resulted in increased differentiation of stem cells into progenitor cells accompanied by an overall developmental delay in neuronal differentiation. Medulloblastoma generated by Hedgehog activation (through inactivation of the negative Hedgehog regulator Ptc1) in both cell types cannot be blocked by Notch inactivation. Furthermore, medulloblastoma of Ptc1lox/lox;RBP-Jlox/lox;GFAP-Cre and those of Ptc1lox/lox;RBP-Jlox/lox;Math1-Cre mice are identical in incidence as well as histology to the tumours in which only Hedgehog signalling is activated. This implies that even though Notch signalling plays an important role in cerebellar stem cells it is not required for the initiation and development of Hedgehog induced medulloblastoma. Therefore it may be crucial to consider the Hedgehog status of patients in order to interpret clinical data of Notch pathway inhibitors and even more importantly these results suggest that determining the Hedgehog status might be crucial before treatment of medulloblastoma patients with Notch pathway inhibitors.

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