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Learning Outcomes 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. Outline Developmental processes occurring during vertebrate development Axes formation -Signalling centres Left right asymmetry Anterior-posterior axis formation Animals must be specified in three dimensions The germ layers are created during gastrulation Lecture E01 The germ layers form different tissues Basic morphogenic processes are similar between animals Gastrulation in a fly FlyBase 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) Organisers are involved in body axis formation in vertebrates Signalling centres instruct surrounding cells to form tissues Node graft Two headed cow... Genetic determinants involved in body axis formation in mammals The major signalling centre in vertebrates is the node Node Chicken Human Question: How does the node pattern? 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 Cells signalling through transmembrane receptors FGF Extracellular FGFR Intracellular SHC Grb2 RAS SOS RAF MEK P MAPK 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 Gradients of secreted proteins produce the different germ layers Left-right asymmetry of internal organs Lungs Heart Gut looping Liver http://mekhala.blogspot.com/2007_11_25_archive.html Left-right patterning asymmetric 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 Gut looping, heart looping chick In situ hybridisations of left-right asymmetry genes Node and cilia How to break symmetry The node spins anterior R L posterior Loss of left-right asymmetry leads to disease Situs inversus •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 Homeotic genes 3’ 5’ Colinearity: location on the chromosome corresponds to the spatial expression pattern Temporal and spatial colinearity: order of Hox genes on the chromosome follows the antero-posterior body axis. How do we get anterior-posterior axis: the HOX Genes!! Veraksa, Del Campo & McGinnis. 2000. Mol. Genet. Metab., 69, 85-100. Combinations of Hox genes specify the development of the anterior-posterior axis Embryonic structures Adult organs Hox gene expression follows the somite bondaries Film of somitogenesis When Something Goes Wrong… * Thoracic vertebra Extra rib Lumbar vertebra The function of Homeotic genes in mammals is similar to in flies: the KO of hoxc8 in mouse causes an homeotic transformation: the first lumbar vertebra forms a rib. 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 somite develops into sclerotome and dermomyotome notochord patterns neural tube Diseases associated with Hox gene mutations 1. Hand-foot-genital syndrome (Hox A11-13 deletion) 2. Synpolydactyly (HoxD13 deletion) 3. Cleft palate 4. Brain abnormalities 5. Leukemia (Hox D4) 6. Retinoic acid, which causes birth defects, affects Hox genes Polydactyly Teratology Lecture 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
