Limb Development and Malformations Flashcards
Malformation v Deformation/Disruption
Malformation- internal problem w/ abnormal formation of tissues
Deformation- tissue abnormality w/ extrinsic cause; disturbance is just worse version
Syndrome
Association
Sequence
Syndrome- complex of malformation w/ KNOWN genetic cause
Association- complex of malformations w/ UNKNOWN genetic cause
Sequence- 1 event triggers others in cascade
What is the most common congenital malformation?
Heart defects (1/100)
What germ layers are the limbs derived from?
muscle- somites (mesoderm)
cartilage/bone - lateral mesoderm
epidermis- ectoderm
What signals the proximal-distal axis of limbs?
-Apical ectodermal ridge (AER) is thickening on ea bud that releases FGFs –> proximal distal OUTGROWTH
- Forelimb = Tbx5 inc transcription/expression of FGFs
- Hindlimb = Pitx1 –> Tbx4 inc transcription/expression of FGFs
What defines where the limb buds form?
Hox gene patterns along anterior-posterior axis
Limb Malformations (6)
1- syndactyly - fused digits
2- polydactyly - extra digits
3- brachydactyly - short digits
4- phocomelia - missing proximal elements
5- amelia - absent limb
6- club foot - foot in and down (MOST COMMON)
Sonic Hedgehog/Smoothened Signal Pathway
- Patched blocks smoothened
- Shh binds to remove the repression of Patched –> releases Smoothened
- Leads to cascade which eventually changes expression of Gli transcription factors
- *So Gli is downstream target of Shh
- *Does so w/ help of primary cilia
What signals the anterior-posterior pattern of limbs?
- Zone of Polarizing Activity (ZPA) is in posterior part of limb bud and its cells express Shh –> graded distribution of Shh –> digit proliferation
- Later, BMPs expressed in webs b/n digits –> apoptosis/cell death to separate out digits
Mutations in Tbx5 Cause…
Upper limb defects
Mutations in Pitx1 Cause…
Lower limb defects
Mutations in Hox Genes Cause…
Digital abnormalities
Mutations in Gli3, Shh or Primary Cilia Cause…
Polydactyly
