Lecture 13- Chondrogenesis
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What are 2 structures that derive from the somite?
• Skeletal muscles of the trunk and limbs 2. The axial skeleton
What 3 tissues are responsible for bone formation and what bones do they form?
• Cranial neural crest cells: responsible for the formation of the craniofacial skeleton • Somites`: responsible for axial skeleton formation (patterning genes are pax and scleaxis genes) • Lateral mesoderm: responsible for the formation of the limb skeleton
What is chondrogenesis?
The formation of bones involves the formation of the cartilage matrix which is progressively replaced by bones
What are the origins of the axial, appendicular and craniofacial skeleton?
Axial skeleton forms from the paraxial mesoderm Appendicular skeleton forms from the lateral mesoderm Craniofacial skeleton forms from neural crest cells
What parts of the axial skeleton do alizarin and alcian blue stain?
Alizarian stains bones red, alcian blue stains cartilage blue
What genes are organised in a sequential manner along the chromosomes?
Hox genes
Explain the collinearity manner of hox gene expression
• Each gene is organised within the chromosome in a 3 prime to 5 prime manner that mimic their A/P expression pattern • The genes present in 3 primes are the genes that expressed the earliest and the most anteriorly • The genes present in 5 primes are expressed later and more posteriorly
Define the Hox code
The positional information that dictates what type of vertebrae is formed is dictated by the combination of Hox genes expressed at any one time within the somite
What dictates the specificity of the various vertebrae present along the axial skeleton?
The combination of Hox genes present/expressed within the somites
What type of correlation is there between the organisation of Hox genes along the chromosomes and the pattern of expression?
Spacial and temporal
How many cervical vertebrae do mammals have and how did mammals evolve to have similar number but different size of vertebrates?
Mammals have 7cervical vertebrate One hypothesis is that Hox genes (in additional to controlling A/P identity) control cell proliferation
What are the 3 steps leading to axial skeleton formation?
• Sclerotome induction- (specification of the somitic cells to first form the axial skeleton) • Cartilage formation = chondrogenesis (leads to the formation of cartilage model) • Ossification of axial skeleton = osteogenesis (replacing cartilage by bone)
Outline the steps of chrondrogenesis by which the cells loose their pluirpotency
• Somite stem cells undergo specification into • Sclerotomal cells which undergo determination into • Chondroblasts which undergo differentiation into • Chondrocytes which mature into • Hypertrophic chondrocytes
What does the axial skeleton originate from?
The axial skeleton originates from the sclerotome which forms from ventral somatic cells undergoing EMT
What do sclerotomal cells express?
Pax1 and Pax9
If Pax1/9 are important in sclerotome formation, when should they be expressed?
Should be expressed at the time the sclerotome forms
What was observed in in-situ hybridisation of Pax1/9 genes?
Observed that Pax1/9 genes are exclusively expressed in the ventral part of the developing somite at the time the sclerotome is forming Pax1 appears to be expressed more medially, whereas Pax9 is expressed more laterally
What can be observed/concluded from a Pax1 mice KO?
• Mice are viable • Have abnormalities in the vertebral column, the sternum and the scapula • Suggesting Pax1 may not be essential in the formation of the axial skeleton • Shows functional redundancy: in the absence of Pax1, Pax9 can carry out some or all of the functions of the missing gene
What can be observed/concluded from a Pax9 mice KO?
• Mice die shortly are birth • Have abnormal craniofacial, visceral and limb skeletogenesis • Shows functional redundancy: in the absence of Pax9, Pax1 can carry out some or all of the functions of the missing genes
What can be observed/concluded from a Pax1/9 dual mice KO?
• Mice completely lack derivatives of medial sclerotome: vertebral bodies, intervertebral discs, proximal ribs • Therefore Pax1 or Pax9 is required for medial sclerotome development • The phenotype of Pax1/9 dual mutant demonstrates essential role in axial formation as animals lack large parts of the axial skeleton
Why bones originate from the ventral medial and lateral sclerotome and how was this identified?
Vertebral bodies, intervertebral discs, proximal ribs as these are affected in Pax1/9 gene KO
What bones originate from the dorsal sclerotome and how was this identified?
Neural arches as these are not affected in Pax1/9 gene KO
What bones originate from the dermal myotome and how was this identified?
Distal vertebral and sternal ribs. Identified through cell fate mapping
What 2 signalling molecules control Pax1/9 and therefore the formation of the sclerotome?
Shh and BMP4