1. Chapter 21. Development of Multicellular Organisms
Sydney Brenner, 1960

2. Mutation vs. variation
Mutation
Variation
Mutation

3. Types of mutation 1. No phenotype -Amorph 2. Loss of function -Null
-Hypomorph
3. Gain of function
-Hypermorph
-Antimorph (dominant negative)

4. 1. Robust model for the behavior of individual and identified cells 1000 somatic germ cells
2. Convenient model for genetics  Single heterozygote worm can produce homozygous progeny
3. Cell fates and lineages are almost perfectly predictable

5. Mechanisms for C. elegans development
Polarity formation by maternal effectors
Cell-cell interactions to make complex patterns
Heterochronic genes
Apoptosis

6. 1. Maternal effect genes
mRNA from mother is asymmetrically distributed along anteroposterior axis Par (partitioning defective) genes bring P granules to posterior pole One cell having P granule give rise to germ cells

7. 2. Cell-cell interactions to make complex patterns

8. 2. Cell-cell interactions to make complex patterns
P2-EMS interaction:
1. Mom mutants without gut
-Mom gene (Wnt) expressed in P2 cell
-Frizzled gene (Wnt receptor) expressed in EMS cells
2. Pop mutants with extraguts
-Pop genes encode LEF-1/TCF homolog
-Reduced pop activity  gut
-Increased Pop activity  muscle

9. Cells change over time in their responsiveness to signals
At four cells
Anterior cell specification  depend on Notch signals
At 12-cell stage, both Aba and Abp progenitors exposed to Notch signals
 Granddaughter of Aba cells induce pharynx
 Granddaughter of Abp cells unresponsive to Notch

10. Heterochronic genes control the timing of development
Heterochronic phenotypes:
The cells in a larva of one stage behave as though they belong to a larva of a different stages, or cells in the adult carry on dividing as though they belonged to a larva
lin-4 for the transition larval stage1  3
let-7 for the transition late larva  adult

12. Apoptosis 1030-131 Cell death abnormal gene
-ced-3, ced-4, egl-1 (caspase, Apaf-1, BAD homolog)  cause cell death
-ced-9 (Bcl-2 homolog)
 repress cell death

13. The Nobel Prize in Physiology or Medicine 2002
"for their discoveries concerning 'genetic regulation of organ development and programmed cell death'"
                          
Sydney Brenner
H. Robert Horvitz
John E. Sulston
    1/3 of the prize
United Kingdom
USA
The Molecular Sciences Institute Berkeley, CA, USA
Massachusetts Institute of Technology (MIT) Cambridge, MA, USA
The Wellcome Trust Sanger Institute Cambridge, United Kingdom
b (in Union of South Africa)
b. 1947
b. 1942

14. Drosophila and the molecular genetics of pattern formation: Genesis of the body plan
Seymor Benzer

16. Overall procedures

17. Overall procedures

18. Syncytial Specification
Pole cells

19. Maternal effects Egg polarity determination A-P and D-V axis
Cytoplasmic bridges

20. Egg polarity genes (Maternal effectors)

21. Egg polarity genes (Maternal effectors)

22. Dorsoventral axis Dorsal protein (NF-kB):
-Dorsally, the protein is present in the cytoplasm and absent from the nuclei; ventrally, it is depleted in the cytoplasm and concentrated in the nuclei.
-Toll gene controls the redistribution

23. Dorsoventral specification
Dorsal protein concentration
High  activate twist, repress dpp (decapentaplegic)
Intermediate  sog (short gastrulation)

24. Dorsolventral specification
Fate map

25. Distribution of twist in mesodermal cells

26. Anteroposterior specification
Maternal genes, bicoid, nanos
Segment genes refine the pattern
Zygotic genes
Six gap genes: Coarse subdivision
Pair rule genes: Segment alteration
Segment-polarity genes:
Homeotic selector genes

27. Anteroposterior specification
Krupel lacks 8 segments (T1-A5)
Even-skipped (eve) lacks odd- numbered parasegments
Fushi tarazu (ftz) lacks even-numbered parasegments
Gooseberry posterior half is the mirror image of anterior half

28. Pair rule genes Formation of parasegments
Expression pattern of ftz (brown) and eve (gray)

29. Segment polarity genes
Forms parasegments polarity
Involves cell-cell interactions
Associated with two signaling pathways
Wnt
Hedgehog

30. Regulatory hierarchy

31. The Nobel Prize in Physiology or Medicine 1995
"for their discoveries concerning the genetic control of early embryonic development"
                          
Edward B. Lewis
Christiane Nüsslein-Volhard
Eric F. Wieschaus
    1/3 of the prize
USA
Federal Republic of Germany
California Institute of Technology Pasadena, CA, USA
Max-Planck-Institut für Entwicklungsbiologie Tübingen, Federal Republic of Germany
Princeton University Princeton, NJ, USA
b d. 2004
b. 1942
b. 1947

32. Homeotic mutations

33. Homeotic selector genes
Hox gene complex
Antennapedia complex
Bithorax complex
Contain homeodomain
60 amino acids
DNA binding region
Regulate positional information

34. Hox gene complex

35. Expression of hox gene complex

36. Hox gene complex

37. Comparison of hox gene expression

38. Comparison of hox gene expression

39. Organogenesis and patterning of appendage

40. Methods in fly genetics: Somatic mutations
Mosaic

41. Methods in fly genetics: Enhancer trap

42. Imaginal discs Groups of cells set aside undifferentiated
19 discs (9 pairs + 1 genital)
Develop into organs such as leg, wing, eyes etc.

43. Specific ID genes define organs
Distal-less  expressed in appendages
Pax-6  expression in eyes

44. Wing formation Sector formation in wing disc Four compartments foms
engrailed, apterous genes are involved

45. Wing formation

46. Wing formation
(A) The shapes of marked clones in the Drosophila wing reveal the existence of a compartment boundary. The border of each marked clone is straight where it abuts the boundary. Even when a marked clone has been genetically altered so that it grows more rapidly than the rest of the wing and is therefore very large, it respects the boundary in the same way (drawing on right). Note that the compartment boundary does not coincide with the central wing vein. (B) The pattern of expression of the engrailed gene in the wing, revealed by the same technique as for the adult fly shown in Figure 21–40. The compartment boundary coincides with the boundary of engrailed gene expression.

47. Limb formation

48. Bristle formation achaete, scute genes -HLH -Proneural genes
Scute expression in wing disc

49. Lateral inhibition
Notch-delta

50. Lateral inhibition Notch somatic mutation Loss of lateral inhibition
Bristle patches

51. Bristle formation
Numb gene
-Block Notch gene activity

52. Bristle formation Planar polarity genes
Orienting bristle backward position
frizzled proteins  control planar polarity
dishevelled  downstream of frizzled

53. Bristle formation