Konstantinidou, C; (2015) Stage-specific response of NC lineages to genotoxic stress. Doctoral thesis , UCL (University College London.

Abstract

The enteric nervous system (ENS) constitutes a gut-intrinsic network of interconnected ganglia which control multiple aspects of gastrointestinal activity, including motility, secretion and blood flow. Most enteric neurons and glia are derived from a relatively small population of neural crest (NC) cells which originate primarily from the vagal NC and migrate ventromedially to invade the foregut mesenchyme. Within the gut microenvironment, ENS progenitors receive signals that allow them to survive, proliferate, differentiate and migrate extensively, giving rise to a uniformly distributed population of enteric neurons and glia. So far, most developmental studies have explored the behaviour of ENS progenitors within the gut wall, but little is known about the properties of NC cells prior to foregut invasion. To explore the spatiotemporal dynamics of ENS development, we conditionally inactivated Geminin (Gem), a mouse gene with fundamental roles in genome integrity and cell fate decisions. Gem deletion from pre-enteric NC cells results in extensive DNA damage followed by P53-mediated apoptotic cell death and intestinal aganglionosis. In contrast, ablation of Gem from enteric NC cells has minimal effects on ENS development. To determine whether ENS lineages display a stage-specific sensitivity to generic genotoxic stress, we monitored the in vivo response of NC cells to γ-irradiation at different developmental stages. While both pre-enteric and enteric NC cells where characterised by robust DNA damage response, pre-enteric NC cells displayed a far greater apoptotic response relative to their enteric counterparts. These experiments reveal a previously unknown spatiotemporal sensitivity of NC cell lineages to genotoxic stress and provide an experimental paradigm for understanding the mechanisms by which DNA damage from genetic or environmental insults leads to congenital ENS deficits. Our studies allow us to draw general conclusions as to how DNA damage and fundamental developmental processes are integrated in vertebrate embryos.

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