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Pattern Formation
Organisation of the Body
| Question | Answer |
|---|---|
| Patterning events in early development | A group of cells are set aside and then specified e.g. mesoderm, somites They are then patterned in 3D, involving cell growth, movement and differentiation regulated by signalling centres Different cells then become committed to different specific cells |
| Molecules regulating mesodermal induction in xenopus | Presumptive ectoderm sits at the top of the embryo If this is transplanted above endoderm it forms mesoderm - mesoderm is signalled by endoderm Signalling forms ventral and caudal mesoderm Dorsal mesoderm forms organiser region |
| Spearman's organiser graft | Transplantation of organiser region to other side of embryo leads to formation of patterned dorsal axis Most of secondary axis is produced from host tissue |
| Cell Cell signalling in patterning | Requires one or more spatially localised signalling centres Limited number of signalling molecules is used and reused Cells respond in cell specific ways to these signals activating a cell specific transcription - they are already partially specified |
| Developmental signals | Sonic Hedgehog signalling Wnt signalling TGF-beta signalling (including BMP) Receptor tyrosine kinase signalling Notch signalling Toll signalling - innate immunity |
| Use of limbs as a model for pattern formation | Vertebrate limb is highly patterned with many axis It is dispensable Defects are easy to recognise Many rare human genetic disorders affect limb patterning - have models in other vertebrates as mechanisms are conserved |
| Development of the human limb bud | Upper limb develops just before the lower limb Occurs between 4-8 weeks |
| Gross anatomical changes - cartilage | Bud - lateral plate mesoderm covered in cuboidal epithelium which forms epidermis Mesenchymal core forms hyaline cartilage models at 6th week Complete set of cartilage models by end of 6th week Structures similar to later development by 8th week |
| Ossification | Primary ossification centres in all bones by 12th week - endochondral ossification At birth central diaphysis is usually completely ossified but not epiphysis - secondary ossification centres form shortly after, epiphyseal plate still growing |
| Somatic mesoderm migration | Somatic mesoderm (hypaxial mesoderm) invades limb bud during 5th week Forms dorsal and ventral condensations that give rise to mainly extensor and flexor muscles respectively |
| Ingrowth of spinal nerve axons | Ventral branches of spinal nerves grow in upper C5-T1/2 and lower L2-S2 Branches form plexus - brachial (upper) Lumbosacral (lower) Make dorsal and ventral branches Innervate nearest unoccupied muscle - rostral nerves e.g. C5 first-more proximal muscle |
| Rotation of limbs | Ectodermal dermatomes from body wall are recruited as limb extends involving C4, S3 etc Between 6-8 weeks limbs rotate around long axis Medial (180 degree) rotation of lower limb and less pronounced lateral rotation of upper limbs-spiralling dermatomes |
| Classes of limb abnormalities | Reduction defects e.g. Amelia, meromelia Duplication defects - polydactyly Malformations - syndactyly |
| What triggers limb bud formation | Multiple signalling centres e.g ZPA Limited range of signalling models Animal models and human disease used to study |
| Conservation of basic limb plan | Vertebrates tend to have similar body plans with different structures Similar processes in body plan formation- can be used to study human development |
| Temporal order of formation | Proximal to distal order of cartilage formation is similar in mouse and chick Occurs faster in chick, but proximal structures form first in both |
| Positioning of the limbs - FGF10 | FGF10 is expressed in lateral plate mesoderm that will form limbs FGF10 expressing cells can induce ectopic limbs, but only at the D/V boundary - limb line |
| Positioning of the limbs - Hox genes | E.g. retinoic acid, Hoxb5 mutant mouse - more rostral forelimb Models Sprengel deformity Hox genes expressed in the leg of a balloon frog (treated with retinoic acid) forms legs on the tail |
| Positioning of the limbs - Tbx transcription factors | Tbx5 expressed rostrally - forms forelimb Tbx4 caudally - forms hindlimb Can create mixed limbs by transplanting Tbx4 and Tbx5 producing cells |
| Apical Ectodermal Ridge | Forms in 5th week due to FGF10 Growth maintained by FGF4 and FGF8 from AER AER induces growth in underlying mesenchyme - signals back to AER in positive feedback loop FGF signal from AER induces distal structures |
| Experiments on AER | Removal of AER leads to truncation of distal structures AER from early limb onto late limb - can duplicate limb AER from late limb onto early limb - only distal structures form Action of AER seems related to age |
| Amelia, Meromelia and Phocomelia | Amelia - no limbs formed Meromelia - some limbs formed - defects in Tbx 3 and 5 genes Phocomelia - due to thalidomide- may block cell growth in AER so all resulting cells have a distal fate (remain in contact with AER in development) |
| Zone of Polarising Activity | Retinoic acid was first thought to be the candidate signal from the ZPA Now Shh is most likely initial signal, which may induce TGF-beta signals If ZPA transplanted to other side of limb bud a mirror image of limb develops Patterns rostral/caudal axis |
| Shh in ZPA | Involved in pattering wing of flies and chicks Expressed in the ZPA Specifically in caudal part Left right asymmetry, neural patterning and somite patterning |
| Experiments supporting Shh as ZPA morphogen | Expressed in posterior part of limb bud in all vertebrates Can induce mirror-image limb duplications in drosophila Turns on transcriptional programs dependant on conc Transplanting to opposite side of limb produces mirror image 123321 |
| Polydactyly | Too many digits form Seems related to how shh concentrations are interpreted |
| Role of Hox genes in patterning | Transcriptional factors Arranged on chromosomes in expression order High functional conservation in homologues in A/P patterning 4 complexes in mammals gives redundancy Additional genes in mammals - all on right hand side of genes to pattern limb |
| Hox gene expression in chick wing bud | Some hox genes are only expressed at distal ends of limb buds E.g. HOXa13 on upper limb and HOXd13 on lower limb Specifies V/C axis |
| Synpolydactyly | Formation of extra digits Due to Hoxd14 and Gli3 mutations Specification of rostral/caudal axis identity changes |
| Hand-foot genital syndrome | Due to a Hoxa13 mutation Causes truncation of developing limbs - only distal structures as Hoxa13 is only expressed at distal end of limb bud Can affect hands, feet and genitals |
| Cleft foot and hand | Ectrodactyly - 3rd metacarpal and phalangeal bonds almost always absent Other digits often fused - syndactyly Patterning defect typically unknown, but some rare genetic causes now identified e.g. Wnt10B |
| Formation of the digits | A combination of apoptosis and digit growth Cutaneous syndactyly - failure of apoptosis so digits are still fused |
| Dorsoventral Polarity | Rotate ectoderm 180 degrees - invert D/V axis - programmed by ectoderm Wnt7a induces Lmx1 activity in dorsal mesenchymal cells of mesoderm - transcription factor causes dorsal identity Take ectoderm from dorsal to ventral side changes the axis in chicks |
| Nails-patella syndrome | Human Lmx1 mutants Dorsal structures do not form normally - patella and nails Rotation of the ectoderm puts them on the ventral side |
| Evolution of limb patterning | Genes identified in drosophila - Hox genes Gene functions tested in chick and mouse Human mutations confirm models and identify differences - often uses same genes and mechanisms as development is highly conserved |
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