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Life as a worm-- the nematode C. elegans

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

Life as a worm-- the nematode C. elegans

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

Hermaphrodites do it by themselves

An entire C. elegans hermaphrodite worm consists of exactly 959 cells EVERY SINGLE TIME, allowing one to follow the cell lineage.

Here’s how it works

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

Most lineages do not consist of single tissue types but the germline and the gut both arise from single founder cells

Most lineages do not consist of single tissue types but the germline and the gut both arise from single founder cells

the secret of embryonic development Within this lineage is the secret of embryonic development

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

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

One mechanism is through asymmetric segregation of determinants How can lineage control cell fate? One mechanism is through asymmetric segregation of determinants

segregated into one cell at the 16-cell stage. That cell is the A determinant within the P granules is asymmetrically segregated into one cell at the 16-cell stage. That cell is the progenitor of the germline! DNA P granules Gilbert 8.33

In par mutants P granules are found in ALL daughter cells wildtype par-3 mutant

Mutations can alter lineages in many ways

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

Changes in the pattern of cell division Example #1- lin-22 Changes in the pattern of cell division lin-22 is homologous to the Drosophila pair-rule gene hairy

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

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

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

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

Vulva Formation in C. elegans A paradigm for organogenesis One inducing cell Three receiving cells 22 cells One complete organ 28

The key players One gonadal anchor cells (AC) 6 vulval precursor cells (VPCs) 30

Cell ablations help define the key players

The anchor cell (AC) signals to the vulval precursor cells (VPCs) to adopt vulval fates

All cells are created equal (or, the road to fame is paved with dead bodies)

The “bag of worms”

The vul mutations helped define the RTK-Ras pathway, which is mutationally activated in about half of all human tumors

This pathway’s so important in Cancer it got 2 spots on this Table! Here’s Notch

Does this remind you of anything we learned earlier?

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