Lecture 13 Chrondogenesis
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The genes that regulate organogenesis/cartilage/bone derive from?
craniofacial skeleton, axial skeleton and limb skeleton
Each bony element from the axial skeleton derives from the same…
Somitic domain
How do the bony elements differ?
Not identical as they differ depending on position along AP axis
What do Hox genes control
Hox genes expressed control antero-posterior patterning of somites i.e. control segment identity
Hox genes expressed control …. of somites i.e. control …
Hox genes expressed control antero-posterior patterning of somites i.e. control segment identity
Why did mammals evolve to have the same number of vertebrae, but different sized vertebrae?
Mammals evolved to have the same number, but different sized vertebrae because Hox genes also control cell proliferation. Evidence from studies linking childhood cancer with defect in Hox gene regulation and homeotic transformation (i.e. formation of ribs on cervical vertebrae).
What are sclerotome?
Proliferating progenitor cells
What are the three main steps which lead to the formation of axial skeleton
• Sclerotome induction - Sclerotome are proliferating progenitor cells • Cartilage formation = chrondogenesis • Ossification of axial skeleton = osteogenesis
Describe the pathways of how a stem cell forms a myofiber or a hypertrophic chondrocyte
See notes
Where are Pax3/7 expressed?
Dorsally
Where are Pax1/9 expressed?
Ventrally
Describe where the Pax genes are expressed during sclerotome formation
• Pax1/9 are expressed in the ventral somite as it undergoes EMT • Pax1 is expressed more medial in sclerotome cells lying right next to neural cord and notochord • Pax9 is expressed more distal sclerotome cells near the outside of the forming embryo and closer to the lateral mesoderm.
TYPICAL EXAM Q: What is the experimental evidence that a particular gene is involved in a particular process?
Must discuss GOF assays (gene/mRNA/protein placed into ectopic place to see if it can instruct cell fate) and LOF assay (KO gene or protein/knock down mRNA encoded by gene).
What does the phenotype of Pax1-/-;Pax9-/- demonstrate?
That these genes have an essential role in axial skeleton formation
Compare WT to Pax1-/-;Pax9-/-
The photo shows that the neural arches have lost their middle section and are smaller. The vertebral body has been lost. There is a loss of intervertebral disc. So it can be concluded Pax1/9 play an essential role in formation of axial skeleton
TYPICAL EXAM Q: What is experimental evidence that Shh regulates sclerotome induction?
We haven’t been told this but need to combine different components of the lecture. E.g. LOF on pax1 or pax9, or genetic knock downs. Include how mice lacking shh do not get pax1 or pax9 induction.
Besides Pax1/9, what else play a role in sclerotome formation?
Scleraxis
Shh and BMP4 and involved in the … and … of Pax1/9 expression
Induction Patterning
Describe the induction and patterning of Pax1/9 expression
INDUCTION: - i.e. transcriptional upregulation. Shh induces a gene, which means that the signal is received by the responding sclerotome cell to initiate Shh signalling cascade. Gli activators go into nucleus and bind to Pax1/9 promotors to turn on transcription of pax1/9 genes PATTERNING: - i.e. how in a field of cells, you begin to break symmetry - here symmetry is broken along the medial lateral axis
What is the cartilage matric made up of?
Proteins including collagen II/IX/XI
Disorders affecting differentiation of cartilage and bone cells have features of both…
Dysostosis (defective formation of bone) and osteochondrodysplasia (defective bone/cartilage development).
Describe the Wnt signalling in chrondogenesis
A bistable switch is regulated by Wnt signalling. 2 cells types form depending on whether mesenchymal condensations are switched on or not: • If wnt is inhibitory, chondrocytes are formed • If wnt is not inhibitory, osteoblasts are formed