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Pathways Mediating Apoptosis Upon Developmental Defects

Beira, JMV; (2013) Pathways Mediating Apoptosis Upon Developmental Defects. Doctoral thesis , UCL (University College London).

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The maintenance of functional tissues and organs in multicellular organisms relies on the controlled elimination of defective cells. Clearance of abnormal cells is crucial to maintain tissue homeostasis during embryonic development and throughout life. The apoptosis machinery has been relatively well characterized, yet the current understanding of the upstream signals instructing cell death is fragmentary. Epithelial cells in the Drosophila embryonic epidermis undergo apoptosis when tissue integrity is compromised. The absence of the apical determinant crumbs leads to widespread activation of the JNK stress pathway, which upregulates the pro-apoptotic gene reaper in the ventral epidermis. Cells in the dorsal domain are protected from apoptosis despite JNK activation throughout the epidermis. The interplay between JNK and Dpp signalling, which functions in the dorsal territory, has elucidated a protective mechanism counteracting JNKdependent apoptosis, via reaper repression. JNK- and Dpp-dependent inputs on the reaper promoter have been investigated using transcriptional reporters and mutations of predicted binding sites. The next challenge in this area will be to identify the signals that function upstream of JNK activation, as they remain poorly understood. Another situation leading to cell death concerns cell mis-specification, when cells lack an important patterning regulator. Embryos lacking the pair-rule gene fushi tarazu display defects due to death of mis-specified cells. The pathway mediating apoptosis in response to cell mis-specifiation is unknown. In contrast to the loss of epithelial integrity, mis-specified cells do not show JNK activation or reaper upregulation. Importantly, a different pro-apoptotic gene, hid, is required for apoptosis in ftz mutants. Loss of epithelial integrity and cell mis-specification are consequence of defects with different origins. The existence of dedicated cell death pathways responding to these two types of developmental defects may be relevant to protect tissues and prevent disease. The mechanisms that enable defective cells to be eliminated may also function in other organisms, tissues and contexts.

Type: Thesis (Doctoral)
Title: Pathways Mediating Apoptosis Upon Developmental Defects
Language: English
Additional information: Permission for digitisation not received.
Keywords: Apoptosis, Signalling, Drosophila, Epithelial integrity, Cell Death, Cell Mis-Specification, Transcription
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/1415745
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