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Life as a worm-- the nematode C. elegans

Life as a worm-- the nematode C. elegans. This humble animal: Revealed how cell lineage controls cell fate. This humble animal: Revealed how cell lineage controls cell fate Revealed the proteins in the RTK pathway, one of the “ big Five ”. This humble animal:

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Life as a worm-- the nematode C. elegans

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  1. Life as a worm-- the nematode C. elegans

  2. This humble animal: • Revealed how cell lineage controls cell fate

  3. This humble animal: • Revealed how cell lineage controls cell fate • Revealed the proteins in the RTK pathway, • one of the “big Five”

  4. This humble animal: • Revealed how cell lineage controls cell fate • Revealed the proteins in the RTK pathway, • one of the “big Five” • 3. Taught us about programmed cell death, • key to neural development and • mis-regulated in cancer

  5. This humble animal: • Revealed how cell lineage controls cell fate • Revealed the proteins in the RTK pathway, • one of the “big Five” • 3. Taught us about programmed cell death, • key to neural development and • mis-regulated in cancer • Gave us insights that led to the discovery of • both RNAi and microRNAs

  6. This humble animal: • Revealed how cell lineage controls cell fate • Revealed the proteins in the RTK pathway, • one of the “big Five” • 3. Taught us about programmed cell death, • key to neural development and • mis-regulated in cancer • Gave us insights that led to the discovery of • both RNAi and microRNAs • 5. Helped us understand organogenesis • at the single cell level

  7. Life as a worm-- the nematode C. elegans

  8. Fertilized egg to adult in ~2.5 days

  9. Think like a geneticist! If you have a single heterozygous mutant fly or worm, how many generations till you have a homozygous mutant animal? http://www.polleverywhere.com/multiple_choice_polls/3fUwSIjK4zkVqsC

  10. Hermaphrodites do it by themselves

  11. An entire C. elegans hermaphrodite worm consists of exactly 959 cells EVERY SINGLE TIME, allowing one to follow the lineage of every cell in the body. Males have exactly 1,032 cells every single time!

  12. Here’s how it works

  13. Was that too fast? Let’s look a bit more closely

  14. Cell lineage: family trees, cellular style

  15. Most lineages do not consist of single tissue types but the germlineand the gut both arise from single founder cells

  16. Most lineages do not consist of single tissue types but the germlineand the gut both arise from single founder cells

  17. Within this lineage is the secret of embryonic development

  18. Even cell death is programmed into the lineage. C. elegans was used to identify the machinery that regulates programmed cell death (apoptosis) in ALL animals

  19. The Nobel Prize in Physiology or Medicine 2002 "for their discoveries concerning ’ genetic regulation of organ development and programmed cell death'" Sidney Brenner H. Robert Horvitz John Sulston

  20. How can lineage control cell fate? One mechanism is through asymmetric segregation of “determinants” Determinants = mRNAs or proteins That drive cell fate decisions

  21. Remember the P granules and how they are segregated into a single cell at each cell division? This cell is P4, The progenitor of the germline P granules DNA Gilbert 8.33

  22. Scientists then looked for mutatns (the parmutants) in which P granules are found in ALL daughter cells wildtype par-3 mutant

  23. We now know the Par proteins are key to making epithelial cells polarized in all animals Apical Basal Apical-towards the lumen Basal- towards underlying cells Lateral-contacting other epithelial cells

  24. New Biology career option: Worm genealogist But first you must learn to read a cell lineage diagram embryo X X Increasing age of worm 1st stage larva 2nd stage larva

  25. How do we read a cell lineage diagram? What do you think is going on here? embryo X X Increasing age of worm 1st stage larva 2nd stage larva

  26. How do we read a cell lineage diagram? What do you think is going on here? embryo X X Increasing age of worm 1st stage larva 2nd stage larva Branching = cell division

  27. How do we read a cell lineage diagram? embryo What do you think is going on here? X X Increasing age of worm 1st stage larva 2nd stage larva

  28. How do we read a cell lineage diagram? embryo X What do you think is going on here? X Increasing age of worm 1st stage larva 2nd stage larva X= programmed cell death

  29. How do we read a cell lineage diagram? embryo How about here? X X Increasing age of worm 1st stage larva 2nd stage larva

  30. How do we read a cell lineage diagram? embryo How about here? X X Increasing age of worm 1st stage larva 2nd stage larva line ending = cell differentiation

  31. Brenner and his colleagues found that mutations can alter lineages in many ways

  32. Example #1- lin-22 Changes in the pattern of cell division

  33. Example #1- lin-22 Changes in the pattern of cell division lin-22 is the worm version of the Drosophila pair-rule transcription factor hairy

  34. Example #2- lin-14 Changes in the timing of cell division L1 L2 L1 L2 L1 L1 L1

  35. Scientists studying regulation of lin-14 were the first to identify functions for microRNAs

  36. And the heterochronic regulator lin-28 can be part of the recipe for making “induced pluripotent stem cells”

  37. The nematode also provides a great model for organogenesis: e.g., Building the vulva Vulva

  38. Vulva Formation in C. elegans: A model for organogenesis One inducing cell Three receiving cells 22 cells One complete organ

  39. The key players One gonadal anchor cell (AC) 6 vulval precursor cells (VPCs) 1° vulval precursor cell 2° vulval precursor cell 3° vulval precursor cell

  40. Cell ablation helped define the key players

  41. Cell ablation helped define the key players What can we conclude from these experiments?

  42. The anchor cell (AC) signals to the vulval precursor cells (VPCs), telling them to adopt vulval fates Hypodermis (normal skin) Hypodermis (normal skin) Vulva

  43. All cells are created equal Any of the VPCs can adopt 1° and 2° fates to form a vulva

  44. Scientists also isolated “vulvaless mutants” because without signaling from the anchor cell, all cells adopt a 3° fate

  45. Without signaling from the anchor cell, all cells adopt a 3° fate What happens in this scenario?

  46. Without signaling from the anchor cell, a vulva cannot form The “bag of worms” phenotype

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