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Principles of Developmental Biology > Lecture 13- Chondrogenesis > Flashcards

Lecture 13- Chondrogenesis Flashcards

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1
Q

What are 2 structures that derive from the somite?

A
  1. Skeletal muscles of the trunk and limbs

2. The axial skeleton

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2
Q

What 3 tissues are responsible for bone formation and what bones do they form?

A
  1. Cranial neural crest cells: responsible for the formation of the craniofacial skeleton
  2. Somites`: responsible for axial skeleton formation (patterning genes are pax and scleaxis genes)
  3. Lateral mesoderm: responsible for the formation of the limb skeleton
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3
Q

What is chondrogenesis?

A

The formation of bones involves the formation of the cartilage matrix which is progressively replaced by bones

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4
Q

What are the origins of the axial, appendicular and craniofacial skeleton?

A

Axial skeleton forms from the paraxial mesoderm

Appendicular skeleton forms from the lateral mesoderm

Craniofacial skeleton forms from neural crest cells

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5
Q

What parts of the axial skeleton do alizarin and alcian blue stain?

A

Alizarian stains bones red, alcian blue stains cartilage blue

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6
Q

What genes are organised in a sequential manner along the chromosomes?

A

Hox genes

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7
Q

Explain the collinearity manner of hox gene expression

A
  • 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
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8
Q

Define the Hox code

A

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

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9
Q

What dictates the specificity of the various vertebrae present along the axial skeleton?

A

The combination of Hox genes present/expressed within the somites

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10
Q

What type of correlation is there between the organisation of Hox genes along the chromosomes and the pattern of expression?

A

Spacial and temporal

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11
Q

How many cervical vertebrae do mammals have and how did mammals evolve to have similar number but different size of vertebrates?

A

Mammals have 7cervical vertebrate

One hypothesis is that Hox genes (in additional to controlling A/P identity) control cell proliferation

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12
Q

What are the 3 steps leading to axial skeleton formation?

A
  1. Sclerotome induction- (specification of the somitic cells to first form the axial skeleton)
  2. Cartilage formation = chondrogenesis (leads to the formation of cartilage model)
  3. Ossification of axial skeleton = osteogenesis (replacing cartilage by bone)
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13
Q

Outline the steps of chrondrogenesis by which the cells loose their pluirpotency

A
  1. Somite stem cells undergo specification into
  2. Sclerotomal cells which undergo determination into
  3. Chondroblasts which undergo differentiation into
  4. Chondrocytes which mature into
  5. Hypertrophic chondrocytes
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14
Q

What does the axial skeleton originate from?

A

The axial skeleton originates from the sclerotome which forms from ventral somatic cells undergoing EMT

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15
Q

What do sclerotomal cells express?

A

Pax1 and Pax9

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16
Q

If Pax1/9 are important in sclerotome formation, when should they be expressed?

A

Should be expressed at the time the sclerotome forms

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17
Q

What was observed in in-situ hybridisation of Pax1/9 genes?

A

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

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18
Q

What can be observed/concluded from a Pax1 mice KO?

A
  • 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
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19
Q

What can be observed/concluded from a Pax9 mice KO?

A
  • 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
20
Q

What can be observed/concluded from a Pax1/9 dual mice KO?

A
  • 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
21
Q

Why bones originate from the ventral medial and lateral sclerotome and how was this identified?

A

Vertebral bodies, intervertebral discs, proximal ribs as these are affected in Pax1/9 gene KO

22
Q

What bones originate from the dorsal sclerotome and how was this identified?

A

Neural arches as these are not affected in Pax1/9 gene KO

23
Q

What bones originate from the dermal myotome and how was this identified?

A

Distal vertebral and sternal ribs.

Identified through cell fate mapping

24
Q

What 2 signalling molecules control Pax1/9 and therefore the formation of the sclerotome?

A

Shh and BMP4

25
Q

Why are both Shh and BMP4 required in the control of Pax1/9 and therefore the formation of the sclerotome?

A
  • In order to get precise domain expression of various genes during embryonic development, you need a combination of signalling pathways
  • Shh induces the expression of particular genes responsible for the formation of the tissue
  • BMP4 molecules are there to restrict the domains of expression
26
Q

Explain the role of Shh in sclerotome formation

A

Shh emanating from the notochord and acting on the cells located in the ventral part of the somite induces and maintains Pax1 and Pax9

27
Q

Explain the role of BMP4 in sclerotome formation

A

BMP4 blocks the expression of Pax1 into the lateral part of the sclerotome but allow the expression of Pax9 in the lateral sclerotome

28
Q

How do sclerotomal cells differentiate into chondroblasts?

A
  1. Migration of cells around the notochord
  2. Down regulation of Pax1 and Pax9 initiate chondrogenesis
  3. Condensation of cells involves changes in extracellular matrix proteins
29
Q

What is osteogenesis?

A

The replacement of cartilage with bone

30
Q

What are the 2 methods in which osteogenesis can occur?

A
  1. Intramembranous ossification

2. Endochondral ossification

31
Q

Briefly describe the process of intramembranous ossification

A
  • Mainly used for ossification of bones from skull
  • No formation of cartilage prior

Mesenchymal cells - nodules - osteoblasts - osteocytes - bone

32
Q

Briefly describe the process of endochondral ossification

A
  • Used for ossification of most bones (limb)

* Bone develops by replacement of a cartilage model

33
Q

Describe the process of endochondral ossification

A
  1. Chondrocytes mature, stop dividing and become hypertrophic (termed hypertrophic chondrocytes)
  2. Chondrocytes die by apoptosis; blood vessels and osteoblasts enter this space, which will become bone marrow
  3. Osteoblasts replace the disappearing cartilage and form primary ossification centre
  4. Blood vessels enter the epiphyses (ends)
  5. Secondary ossification enters (following the same process) and formed in epiphyses, leaving a cartilage plate (growth place) between epiphysis and diaphysis
34
Q

Where does endochondral ossification not occur?

A

The only area where this process doesn’t occur is the growth plate which plays an important role in the growth of bones in postnatal development

35
Q

What forms from the specification of mesenchymal cells?

A

Mesenchymal condensations

36
Q

What are the two pathways possible from mesenchymal condensations?

A
  1. Under endochondral ossification control, mesenchymal condensations can first form chondrocytes and hypertrophic chondrocytes which will then be replaced by osteoblasts
  2. OR under the control of intramembranous ossification, mesenchymal condensations will form osteoblasts and osteocytes directly
37
Q

What dictates whether endochondral ossification or intramembraneous ossification takes place?

A
  • The balance and timing of Sox9 and Runx2 essentially dictates which process will take place
  • Additional signalling molecules (such as Wnt) favours the intramembranous process and inhibits endochondral ossification allowing the balance to ‘tip’ at a certain time during development
38
Q

Given 2 examples of disorders affected by the differentiation of cartilage and bones

A
  1. Campomelic dysplasia

2. Cleidocranial dysplasia

39
Q

What mutation leads to Campomelic dysplasia?

A

Mutation in Sox9

40
Q

What mutation leads to Cleidocranial dysplasia?

A

Mutation in Runx2

41
Q

Describe the layering pattern in growth plates

A
  1. Germinal zone (containing stem cells)
  2. Proliferative zone (containing chondroblasts)
  3. Zone of maturation (containing chondrocytes and pre-hypertrophic chondrocytes)
  4. Hypertrophic zone (containing hypertrophic chondrocytes)
  5. Bottom of the growth plate, osteoblasts and bones emerge
42
Q

What is caused as a result of a depletion in growth plate layers?

A

Dwarfism

43
Q

What is the growth of long bones dependant on?

A

The growth plate

44
Q

Explain the negative feedback loop which regulates cells in order to maintain a pool of progenitor cells for future bone growth

A
  • A negative feedback loop between Ihh and PTHrP controls chondrocyte differentiation and maturation
  • FGFR3, Ihh and PTHrP act together to ensure a pool of chondroblasts and chondrocytes is maintained whilst the growth plate is producing new hypertrophic chondrocytes for the growth of bones
  • FGFR3 blocks the activity of Ihh which itself is required for the activity of PTHrP
45
Q

Explain the mechanism which regulates cells in order to maintain a pool of progenitor cells for future bone growth

A
  1. As the chondrocytes differentiate into pre-hypertrophic chondrocytes, they begin producing Ihh
  2. Ihh acts on cell present within the perichondrium and will trigger these cells to produce PTHrP
  3. The receptor for PTHrP is only present at the surface of cells that are differentiating into chondroblasts and chondrocytes
  4. So, PTHrP is going to act on chondroblasts and chondrocytes, promoting their proliferation and simultaneously blocking their proliferation into pre-hypertrophic chondrocytes
  5. Therefore, whilst you have cells that are differentiating into pre-hypertrophic and hypertrophic chondrocytes, you are producing Ihh that acts by preventing further cells from undergoing this differentiation process
  6. Consequently, maintaining a pool of progenitor cells for future use
46
Q

What do mutations in FGFR3, Shh or PTHrP result in?

A
  1. Loss of proliferation and increase cell death in the chondroblast population and instead an increased number of cells differentiating into chondrocytes/hypertrophic chondrocytes
  2. This depletes the pool of progenitor cells that will become chondroblasts and overtime leading to depletion of differentiated chondrocytes/hypertrophic chondrocytes
  3. Leading to dwarfism

Principles of Developmental Biology (16 decks)

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