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1. Understand the molecular mechanisms underlying early embryonic development in vertebrates.

1. Understand the molecular mechanisms underlying early embryonic development in vertebrates. 2. Explain, in general, how organizers function to pattern the forming axes of the early embryo.

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1. Understand the molecular mechanisms underlying early embryonic development in vertebrates.

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  1. 1. Understand the molecular mechanisms underlying early embryonic development in vertebrates. 2. Explain, in general, how organizers function to pattern the forming axes of the early embryo. 3. Appreciate the conservation of molecular mechanisms controlling body plan development in different organisms: the case of homeotic genes. 4. Colinearity of the homeotic genes in man. Learning Outcomes

  2. Outline Developmental processes occurring during vertebrate development Axes formation -Signalling centres Left right asymmetry Anterior-posterior axis formation

  3. Animals must be specified in three dimensions

  4. The germ layers are created during gastrulation Lecture E01

  5. The germ layers form different tissues

  6. Basic morphogenic processes are similar between animals Gastrulation in a fly FlyBase

  7. Development in vertebrates is based on cell-cell interactions: groups of cells called organizing centres emit instructive signals that induce and pattern surrounding tissues. The concentration gradient of the (signal) morphogen induces multiple cell choices. (E05)

  8. Organisers are involved in body axis formation in vertebrates Signalling centres instruct surrounding cells to form tissues Node graft

  9. Two headed cow...

  10. Genetic determinants involved in body axis formation in mammals The major signalling centre in vertebrates is the node Node Chicken Human

  11. Question: How does the node pattern?

  12. Genetic determinants involved in body axis formation in mammals Organisers ‘pattern’ surrounding cells and tissues by secreting signaling molecules (proteins) Node cells secretes nodal and noggin and FGF Nodal FGF

  13. Cells signalling through transmembrane receptors FGF Extracellular FGFR Intracellular SHC Grb2 RAS SOS RAF MEK P MAPK

  14. Genetic determinants involved in body axis formation in mammals: Neural tissue Signalling centres instruct surrounding cells to form tissues Node or FGF protein Overlying tissues form a neural tube

  15. Gradients of secreted proteins produce the different germ layers

  16. Left-right asymmetry of internal organs Lungs Heart Gut looping Liver http://mekhala.blogspot.com/2007_11_25_archive.html

  17. Left-right patterningasymmetric signalling from the node The expression of genes on the left side of the embryo leads to a cascade of gene expression and morphogenic changes Nodal Nodal Pitx2 chick Gut looping, heart looping

  18. In situ hybridisations of left-right asymmetry genes

  19. Node and ciliaHow to break symmetry

  20. The node spins anterior R L posterior

  21. Loss of left-right asymmetry leads to disease Situs inversus

  22. Named for mutations that • revealed existence • Bithorax – part of haltere on • 3rd thoracic segment is • transformed into part of a wing • Antennapedia – dominant • mutations transform • antennae into legs • Homeotic mutation is the • transformation of one • segment into another related one

  23. Homeotic genes 5’ 3’ Colinearity: location on the chromosome corresponds to the spatial expression pattern

  24. Temporal and spatial colinearity: order of Hox genes on the chromosome follows the antero-posterior body axis.

  25. How do we get anterior-posterior axis: the HOX Genes!! Veraksa, Del Campo & McGinnis. 2000. Mol. Genet. Metab., 69, 85-100.

  26. Combinations of Hox genes specify the development of the anterior-posterior axis

  27. Embryonic structures Adult organs Hox gene expression follows the somite bondaries

  28. Film of somitogenesis

  29. When Something Goes Wrong… * Thoracic vertebra Extra rib Lumbar vertebra The function of Homeotic genes in mammals is similar to in flies: theKO of hoxc8 in mouse causes an homeotic transformation: the first lumbar vertebra forms a rib.

  30. Summary: patterning of the vertebrate axial body plan gastrulation and organizer activity the four Hox gene complexes are expressed along the antero-posterior axis Hox gene expression establishes positional identity for mesoderm, endoderm, and ectoderm mesoderm develops into notochord, somites, and lateral plate mesoderm mesoderm induces neural plate from ectoderm notochord patterns neural tube somite develops into sclerotome and dermomyotome

  31. Diseases associated with Hox gene mutations Polydactyly • Hand-foot-genital syndrome (Hox A11-13 deletion) • Synpolydactyly (HoxD13 deletion) • Cleft palate • Brain abnormalities • Leukemia (Hox D4) • Retinoic acid, which causes birth defects, affects Hox genes Teratology Lecture

  32. Hox genes and vertebrate segment identity • Hox gene mutations lead to subtle phenotypes • Why?? • Hox genes are used over and over again in the developing • embryo • >>>Multiple phenotypes, multiple cancers Reference book: Developmental Biology, Gilbert

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