03. Stem Cell Niches

• intestinal crypt is the most rapidly self renewing tissue in adults

  • stem cells in the crypt produce all cells in villus and this is shown through lineage tracing
• notch = cell surface protein that binds delta or serrate

  • juxtacrine signalling
• notch is cleaved upon ligand binding which frees the intracellular domain which traffics to the nucleus and binds CSL leading to transcription of notch target genes (HES genes)

  • CSL normally binds a co-repressor but Notch binding displaces this and recruits co-activators
• HES genes are transcription repressors

  • therefore end consequence of notch binding = repression
• notch mediates competitive cell interactions to limit specialisation
• notch binding delta = cell with notch reduces delta expression and has differentiation blocked
• notch binding can be influenced by differential delta expression and post-translational modification of notch receptor
• notch is used to space paneth and stem cells
• deregulation of wnt is the leading cause of colon cancer
• wnt binds cell surface receptor Fz -> activates protein called dishevelled -> inhibits GSK3 -> phosphorylates beta catenin -> targets it for destruction
• if wnt is present, beta catenin is stabilised and enters the nucleus where it binds TCF (displacing co-repressor Groucho) turning on transcription of target genes
• APC regulates beta catenin degradation

  • in APC mutant cells beta catenin is always stabilised even in absence of wnt
• FAP = familial adenomatous polyposis

  • carry one mutant copy of APC