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Vertebrate Limb Patterning

Vertebrate Limb Patterning. Techniques to Study the Regulation of Differentiation During Development. Observation of normal development in animals of different species Reporter genes or other markers to delineate particular cell types Ablation and transplantation experiments

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Vertebrate Limb Patterning

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  1. Vertebrate Limb Patterning

  2. Techniques to Study the Regulation of Differentiation During Development • Observation of normal development in animals of different species • Reporter genes or other markers to delineate particular cell types • Ablation and transplantation experiments • Classical genetics to identify genes in which mutations affect limb development • Loss or gain of function mutations (knockouts, transgenics, injection of sense, antisense or small inhibitory RNAs) (genotype> phenotype) • In vitro organ and cell culture

  3. The developing limb bud is patterned along three axes : Proximal-Distal Dorsal-Ventral Anterior-Posterior

  4. Embryonic Chick Wing (day 10)

  5. Apical Ectodermal Ridge (AER) • Thickened layer of cells at distal tip of developing limb bud • Organizing region • Transient structure

  6. What Directs Limb Development? • The APICAL ECTODERMAL RIDGE (AER) is responsible for the proximo-distal patterning of the limb, which occurs over time through the progress zone • Signals are sent both from the AER to the progress zone, and from the progress zone to the AER

  7. Development of the Chick Limb • As the limb bid grows outward, cells in the progress zone proliferate and acquire a positional value • When cells leave the progress zone, cartilage may begin to differentiate, and other elements gain their positional information

  8. Chick Experiments

  9. What Directs Limb Development? • The ZONE OF POLARIZING ACTIVITY (ZPA) is responsible for antero-posterior patterning of the limb

  10. Grafting Experiments When a ZPA is grafted to anterior limb bud mesoderm, duplicated digits emerge as a mirror image of the normal digits.

  11. What regulates limb bud outgrowth? Placing a bead soaked in FGFs adjacent to chick flank can induce ectopic limbs. Limbs were frequently well developed.

  12. What Genes Are Required for Limb Development? • FGF10 is expressed where limbs normally form. • When cells genetically constructed to secrete FGF10 are placed into the flanks of chick embryos, the FGF10 can cause the formation of an ectopic limb (arrow).

  13. What Genes Are Required for Limb Development? • Knock-out of FGF10 in mice results in lack of limbs!

  14. What Genes Are Required for Limb Development? • FGF8 • Expressed in AER • Is induced by FGF10

  15. What Genes Are Required for Limb Development? • Sonic hedgehog is expressed in the ZPA

  16. What Genes Are Required for Limb Development? • Sonic hedgehog can induce the formation of digits at abnormal locations

  17. What Does this Mean for Humans? Human shh mutation

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