Limb Development Flashcards
What does prenatal thalidomide exposure cause?
Children w/ limb development issues and microphthalmia.
Which mesoderm is responsible for forming the limb muscle? What about the limb skeleton?
Somitic mesoderm = muscle
Lateral plate mesoderm = skeleton
What controls the placement of limbs along the body axis?
Hox gene expression patterning according to the gene’s position on the chromosome.
The boundary between ___ and ___ expression is implicated in the forelimb position.
Hox5 and Hox6
The boundary between ___ and ___ expression is implicated in the hindlimb position.
Hox 9 and Hox10
What 2 processes are involved in the “induction” of limb mesoderm? What is essential for these processes?
- Delamination (of cells from lateral plate)
- Migration (to form limb bud)
Require the presence of fibroblast growth factor (FGF).
If you ectopically express FGF in a chick embryo, what occurs?
You get ectopic limb formation at the site of FGF expression.
How do Tbx4 and Tbx5 appear to influence the function of FGF in limb development?
Tbx5: specifies forelimb
Tbx4: specifies hindlimb
What seems to be the default mature structure for a developing limb?
Forelimb-like morphology.
What is Holt Oram syndrome? How is it caused?
Defects in forelimb structure formation caused by Tbx5 mutations.
What structure is visible on the limb bud? Is it necessary for limb formation?
The anterior ectoderm ridge (AER). Yes, removal halts limb development.
What acts to cause specification of limb identities? Why is the AER required for this?
The underlying mesenchyme specifies identity. The AER expresses Fgf8 which keeps the mesenchyme proliferating.
How does expression of Fgf8 affect the limb bud mesenchyme?
Fgf8 keeps the mesenchyme in a proliferative state, otherwise it would stop growing and begin differentiating.
What happens if you replace early limb bud mesenchyme with late limb bud mesenchyme in a developing limb bud?
You only get the last part of the limb, all the earlier structures are gone.
How are proximal-distal limb fates specified according to the progress zone model?
An intrinsic clock at the leading edge which acts on the mesenchyme along with AER FGFs to change specification at different times.
How are proximal-distal limb fates specified according to the two signal model?
Two gradients. Retinoic acid from the proximal domain and FGF from the distal domain each specify. Middle domain under no influence, specifies itself.
How are positional cues in the developing limb mediated? Is there redundancy?
By Hox genes. These exhibit redundancy, requiring double knockout for loss of function.
In limb development, what does ZPA mean? What is this?
Zone of polarizing activity. Mesenchyme in the posterior limb bud which can specify posterior fates.
What is responsible for causing posterior development in the limb?
Shh expression (in the ZPA).
How is anterior limb specification accomplished? What goes wrong in a mouse with hemimelic extra toes (Hx)?
Anterior limb bud specified by low Shh from the Shh morphagen gradient.
How is AP axis asymmetry/digit identity specified during limb development?
By the duration and concentration of Shh signalling. Shh acts as a morphogen, high in posterior.
Why have snakes lost their limbs?
Because they have expanded expression of HoxC8 and HoxC6 to inhibit Hox5B (limb development) along their entire body.
What is the function if HoxC8 and HoxC6?
To inhibit Hox5B (limb development) expression in the space between the forelimb and the hindlimb.
Do snakes express Shh in their ZPA? Have they lost this ability?
No expression of Shh but they still have the ability.
Interaction between the ___ and the ___ stabilizes limb bud progression.
AER and the ZPA.
What factors establish the Shh morphogen gradient in posterior limb development? What else maintains Shh levels?
Transcription factor dHAND as well as Fgf8. Wnt7a maintains Shh levels.
What effect does BMP have on Fgf8? How does gremlin (Gre) activity effect Fgf8?
Gremlin inhibits BMP, effectively upregulating Fgf8.
Through what pathway do researchers suspect thalidomide acts on limb development?
The cereblon pathway.
