Limb Development Flashcards
What does the musculature arise from?
Myotome of the paraxial mesoderm
What do bones arise from?
From somatic layer of lateral plate mesoderm
What do tendons arise from?
From somatic layer of lateral plate mesoderm
When do the upper limbs form?
24 days
When do the lower limbs form?
25-26 days
Limb buds form deep to what structure?
A thick band of ectoderm known as the apical ectodermal ridge (AER)
What causes the limb bud to bulge outward?
Proliferation and outgrowth of mesenchyme from the later plate mesoderm
What are the three regions of outgrowth in a limb bud?
Stylopod, zeugopod and autopod
What does the stylopod form?
Humerus or femur
What does the zeugopod form?
Radius and ulna + tibia and fibula
What does the autopod form?
Carpals, metacarpals, and phalanges
Tarsals, metatarsals and phalanges
What are the three axes of the limb bud?
Proximal distal (shoulder to digits) Cranial caudal Dorsal ventral (dorsum to palm)
What is the AER and where is it located?
It is a specialized multilayered epithelial structure located along the ridge of each limb bud
What induces the AER?
FGF10
What is secreted by AER?
FGF8
Describe the positive feedback loop of FGF8 and 10
FGF8 is secreted by the AER and stimulates its down stream target FGF10
FGF10 then in turn stimulates AER to produce more FGF8
What is FGF signaling essential for?
The initiation of limb development and regulates the outgrowth of the proximodistal axis
What happens if you completely remove the AER?
Arrests limb development
What happens if the AER is removed at later stages of development?
Loss of more distal elements occurs
What occurs when transplanting an AER?
Can result in supernumerary limbs
What is the cranial caudal axis patterned by?
The zone of polarizing activity (ZPA)
When does restriction of cell fates in the limb bud occur?
Before limb bud outgrowth
What signaling factor is expressed in the ZPA and is sufficient for its function?
Shh
What is the result when the ZPA is grafted to cranial limb bud mesoderm?
Duplicated digits emerge (mirrored)
What is polydactyly?
Presence of supernumerary digits
Inherited as a dominant trait
Overexpression of Shh establishes the second ZPA
Extra digit is incompletely formed and lacks normal muscular development
What are Hox genes?
Paralogs that regulate development and regulate the cranial caudal and proximodistal axes
Hox9-10 paralogs specify what?
Stylopod
Hox11 paralogs specify what?
Zeugopod
Hox12-13 paralogs specify what?
Autopod
Expression of HoxD genes can be correlated with what?
Development of specific elements of the forelimb skeleton
Hoxd9 is within what structure?
Scapula
Hoxd9-10 are within what structure?
Arm (humerus)
Hoxd9-11 are within which structures?
Ulna, radius and proximal carpals
Hoxd9-12 are within which structure?
Distal carpals
Hoxd9-13 are within which structures?
Metacarpals and phalanges
What is brachydactyly?
Shortening of the fibers and toes due to unusually short bones
Genetic changes in the HoxD13 gene of PTHLH
If inherited occurs as autosomal dominant
What is Wnt7a and where is it expressed?
It is expressed in the dorsal ectoderm and is a primary regulator of dorsal fates
What happens when Wnt7a is overexpressed?
Results in dorsalized strucutres
Wnt7a KO mice have what?
Ventralized paws (foot pads form on dorsal surface)
Where is Engrailed (En1) expressed?
In the ventral ectoderm
What is the function of engrailed?
Prevents the expression of Wnt7a in the ventral part of the limb
En1 also restricts positioning of the AER to establish the dorsal ventral axis
Which two signaling factors are important for development of the dorsal ventral axis?
Wnt7a and engrailed
Describe formation of the digits
Removal of interdigital mesenchyme frees the digits and allows mobility
Involves apoptosis and requires BMP signaling
An increase in BMP signaling results in what?
Increase cell death allowing for freeing of the digits
A decrease in BMP signaling results in what?
Decreased cell death (resulting in webbed digits)
When do digital rays in the hand plate form?
By 6th week
When do digital rays in the foot plates form?
By the 7th week
When are separate digits formed?
By the 8th week
Describe development of the limb musculature
Myogenic precursors from the dermomyotome of the paraxial mesoderm migrate into the limb bud —> differentiate into myoblasts —> aggregate and form dorsal and ventral muscle masses in each limb bud
What does the dorsal muscle mass form?
Extensors and supinators of upper limb + extensors and abductors of lower limb
What does the ventral muscle mass form?
Flexors and pronators of upper limb + flexors and adductors of lower limb
When does limb innervation begin?
In the 5th week
What happens are spinal nerves exit the spinal cord?
They split into two branches - dorsal and ventral ramus
What does the dorsal ramus innervate?
Epimere
What does the ventral ramus innervate?
Hypomere and limbs
Muscles originating in dorsal muscle mass are innervated by what?
Dorsal branches of ventral rami
Muscles originating in the ventral muscle mass are innervated by what?
Ventral branches of ventral rami
What provides blood supply to the limbs?
Branches of the intersegmental arteries (arising from the dorsal aorta)
Describe the vascular development in the upper limb
Primary axial artery—> brachial and common interosseous artery —> radial and ulnar arteries (terminal branches)
The primordial vascular pattern consists of what?
A primary axial artery and its branches
Describe the vascular development in the lower limb
Primary axial artery —> deep artery of thigh and anterior and posterior tibial arteries
Describe the venous supply of the developing limbs
Primary axial artery drains into marginal sinus —> then drains into singular peripheral vein —> marginal sinus breaks up —> basilic and cephalic veins develop
How is the limb bud initially oriented?
With the ventral surface facing medially and the dorsal surface facing laterally
Both are continuous with the ventral and dorsal surfaces of the embryonic trunk
Describe upper extremity rotation
Rotates 90 degrees laterally
Flexor = anterior
Extensor = posterior
Describe LE rotation
Rotates 90 degrees medially
Flexors = posterior
Extensors = anterior
What is meromelia?
Absence of part of a limb
Intermediate to late loss of FGF signaling
What is Amelia?
Absence of entire limb
Early loss of FGF signaling
What is phocomelia?
Loss of long bones with hands and/or feet attached close to the body
Partial loss of FGF signaling or Hox disruption due to thalomide
What is adactyly?
Absence of digits
What is syndactyly?
Fusion of digits because digital rays fail to develop
Two types: cutaneous and osseous
What is cutaneous syndactyly?
Webbing between digits due to failure to degenerate likely due to a disruption in BMP signaling (lack of apoptosis)
What is osseous syndactyly?
Fusion of bones (synostosis) due to failure of notches to develop between digital rays
Inherited as an autosomal dominant Hoxd13 mutation
What is erodactyly?
Split hands or split foot anomaly (lobster claw deformity)
Partial absence of FGF8 from AER
Also known as ectodermal dysplasia-cleft lip/palate syndrome (EEC)
What are amniotic bands?
Adhesions between amnion and affected fetal structures
What is bilateral talipes equinovarus?
Club foot
Oligohydramnios reduces fetal movements
Describe the timeline of limb development
4th week: both limb buds present
5th week: hand/foot plates appear and chondrification begins
6th week: digital rays of hands, limb skeleton is cartilaginous
7th week: digital rays of feet, osteogenesis begins, rotation of limbs occur
8th week: separate digits are formed
12th week: primary ossification begins
