Cell Differentiation and Limb Development Flashcards
What is cell differentiation?
- Process of cell changing from one cell type to another.
- Mostly, a less specialised cell to a more specialised cell
What controls cell differentiation?
- Many factors:
- Transcription factors
What are transcription factors?
-Regulators that can act at different stages and in deifferent combination through the path of cell development and differentiation.
How can cell differentiation effect a cell?
- Size
- Shape
- Membrane potential
- Metabolic activity
- Responsiveness to signals
- Different cells have different characteristics despite having the same genome
When does limb development occur?
From week 4-8
What do limbs develop from?
-Small buds of undifferentiated mesoderm cells which are covered by ectoderm
What happens/is visible by end of week 4?
- Limb buds become visible for first time
- Upper limb buds appear first as ridges from ventrolateral body wall
- Lower limb as small bulges
- Lower limb slightly behind, but catches up by end of developmental period
What is the 1st sign of limb musculature?
-Appearance of condensation of mesenchyme near limb buds
What is mesenchyme derived from?
-Dorsolateral or ventrolateral mesoderm cells of the somites
Are their nerves in the early limb bud?
NO
What do limb buds consist of?
- Mesenchymal core (from somatic layer of lateral plate mesoderm)
- Covered by layer of cuboidal ectoderm
What does the ectoderm do at the distal end of the limb bud and why is this area different?
- Forms apical ectodermal ridge
- This has inductive relationship with mesoderm and remaind undifferentiated
What is the importance of the AER?
- As limb grows the cells furthest from AER begin to differentiate into cartilage and muscle.
- Without AER limbs fail to develop as it is a key signalling centre
What initiates limb outgrowth?
FGF 10
What does the position of AER correspond to?
-Border between dorsal and ventral ectoderm
What is a difference in how UL and LL development is controlled?
Different factors designated to UL and LL
- TBX-5 in UL
- TBX-4 in LL
Describe relationship between mesoderm and ectoderm interaction and its importance?
- Essential
- AER-promote mitosis and prevents differentiation
- Although AER is acting on mesoderm, its own existence is controlled by the mesoderm
What happens at week 6 of limb development?
- Terminal portions of buds become flattened: -hand plates and foot plates
- Separated from proximal segments by constriction
- 2nd constriction further divides proximal portion into 2 segments
- Development proceeds proximodistally into 3 components
What 3 portions are limbs split to during week 6?
- Stylopod: humerus and femur
- Zeugopod: radius/ulna and tibia/fibula
- Autopod: carpals,MCP,digits,tarsals,metatarsals
What is FGF 10 and where is it first seen?
A paracrine signalling molecule 1st seen in limb buds
What is FGF family known for?
-Mitogenic activity (inducing cell to begin division via triggering a signal transduction pathway)
What signalling molecules help specify the dorsoventral axis around the AER?
- Radical fringe: expressed by dorsal ectoderm
- Engrailed-1: expressed by ventral ectoderm (TF)
What does AER express for maintenace of undifferentiated zone?
Once ridge is established it expresses FGF 4 and 8
What regulates positioning of limbs along craniocaudal axis and how is this expressed and what does misexpresion lead to?
- HOX genes
- Expressed in overlapping patterns
- Mis expression alters limb position
What does cell death in the AER do during limb development?
- Separates ridges into 5 parts: 5 digits gow out under inlfuence of 5 ridge parts
- Mesenchyme condense to form cartilaginous digits
- By day 56, digit seperation is complete
What regulates limb outgrowth?
-FGF 10
What do FGF 4, 8 and Retinoic acid do?
- FGF 4 and 8 at distal end keep cells undifferentiated
- Retinoiic acid at proximal end starts differentiation into proximal components
What is polydactyly and what causes it and how is it inherited?
- Extra digits
- Defect in mesoderm caused by mutations in HOX genes, Sonic hedgehog or Wnt
- Inherited in humans as genetic recessive trait
When and how does limb rotation occur?
- Week 7
- Upper and lower limbs rotate in opposite directions
How does the UL rotate and why?
- 90 degrees laterally
- Allows extensor muscles to lie on lat and post side, makes thumb lateral and elbow pointing back
How does LL rotate and why?
- 90 degrees medially
- Allows extensor muscles to lie ant., big toe to be medial and knees to face forward
What are some things that may go wrong during limb development?
- Conditions affecting UL more common
- Faliure of formation: amelia, meromelia
- Failure of differentiation: sirenomelia, synostoses
- Duplication
- Overgrowth: hemihypertrophy
- Undergrowth: micromelia
- Contriction band syndrom: would need amputatio nat certain levels
- Generalised abnormalities: marfans, achondroplasia
Describe start of limb bone development?
- As external shape is being established, mesenchyme in the buds becomes condensed
- Cells differentiate into chondrocytes
- At week 6 hyaline cartilage models can be seen
- Areas where chondrogenesis is arrested makes joints
What drives mesenchyme cell differentiation to chondrocytes?
BMP expression
Where do centres of ossification form in long bone?
- Diaphysis
- Epiphysis
By when are primary centres present in all bone?
-week 12
Cartilage growth plate remains
At birth what happens?
- Epiphysis still cartilaginous
- Secondary centres disappear
What happens at puberty?
-Growth plates close
During the bone growth period what does remodelling and why?
-Osteoclasts to retain overall shape and proportion
What does achondroplasia effect?
- Enchondral ossification via cartilage, particularly long bones of arms and legs
- Autosomal dominant mostly, due to specific mutation
How would achondroplasia be diagnosed?
- Ultrasound
- 20 weeks scan when long bones can be measured
What can happen if both parents have the gene?
-1 in 4 chance of lethality
What causes achondroplasia?
Mutation in FGF 3 which normally downregulates cartilage and bone growth and inhibits cell proliferation and differentiation.
-Mutation causes permamnent expression so sreduced chondtrocyte activity
Is there a cure for achondroplasia and what problems may arise?
- NO
- But should be able to live healthy independant life
- Some may get breathing issues, curvature of spine issues or walking issues
- Limb strengthening surgery may be used but is painful and no guarantee it will work
Are recent therapies for achondroplasia looking promising?
- yes eg. vosoritide
- Advances in tech for FGF 3 mutation correction( CRISPR/Cas9) but still not too close (not in clinical trials)
