title: Geminin prevents DNA damage in vagal neural crest cells to ensure normal enteric neurogenesis.
abstract: In vertebrate organisms, the neural crest (NC) gives rise to multipotential and highly migratory progenitors which are distributed throughout the embryo and generate, among other structures, the peripheral nervous system, including the intrinsic neuroglial networks of the gut, i.e. the enteric nervous system (ENS). The majority of enteric neurons and glia originate from vagal NC-derived progenitors which invade the foregut mesenchyme and migrate rostro-caudally to colonise the entire length of the gut. Although the migratory behaviour of NC cells has been studied extensively, it remains unclear how their properties and response to microenvironment change as they navigate through complex cellular terrains to reach their target embryonic sites.
  
  
  
  Using conditional gene inactivation in mice we demonstrate here that the cell cycle-dependent protein Geminin (Gem) is critical for the survival of ENS progenitors in a stage-dependent manner. Gem deletion in early ENS progenitors (prior to foregut invasion) resulted in cell-autonomous activation of DNA damage response and p53-dependent apoptosis, leading to severe intestinal aganglionosis. In contrast, ablation of Gem shortly after ENS progenitors had invaded the embryonic gut did not result in discernible survival or migratory deficits. In contrast to other developmental systems, we obtained no evidence for a role of Gem in commitment or differentiation of ENS lineages. The stage-dependent resistance of ENS progenitors to mutation-induced genotoxic stress was further supported by the enhanced survival of post gut invasion ENS lineages to γ-irradiation relative to their predecessors.
  
  
  
  Our experiments demonstrate that, in mammals, NC-derived ENS lineages are sensitive to genotoxic stress in a stage-specific manner. Following gut invasion, ENS progenitors are distinctly resistant to Gem ablation and irradiation in comparison to their pre-enteric counterparts. These studies suggest that the microenvironment of the embryonic gut protects ENS progenitors and their progeny from genotoxic stress.
authors: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, NW7 1AA, UK.|Present address: MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
authors: Chrysoula
authors: C
authors: Konstantinidou
authors: Department of Physiology, Medical School, University of Patras, Patras, GR 26 500, Greece. taraviras@med.upatras.gr.
authors: Stavros
authors: S
authors: Taraviras
authors: The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, NW7 1AA, UK. vassilis.pachnis@crick.ac.uk.
authors: Vassilis
authors: 0000-0001-9733-7686
authors: V
authors: Pachnis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects*; D017615:Enteric Nervous System / Q000166:cytology* / Q000187:drug effects; D005260:Female; D064248:Geminin / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D009432:Neural Crest / Q000166:cytology*; D055495:Neurogenesis / Q000187:drug effects; D011247:Pregnancy
chemical_list: D064248:Geminin
keywords: Apoptosis; DNA damage; Development; Enteric nervous system; Geminin; Neural crest