Limb Development Flashcards
When does the upper limb form?
Day 24
When does the lower limb form?
Day 25-26
Mesenchymal cells grow out from what section of mesoderm?
Lateral Plate Mesoderm
Limb buds form deep to a thick band of ectoderm called the:
Apical Ectodermal Ridge (AER)
Regions of the limb bud consists of:
- Stylopod: humerus, femur
- Zeugopod: radius & ulna, tibia & fibula
- Autopod: carpals, metacarpals, phalanges; tarsals, metatarsals, phalanges
What are the 3 axes of the limb bud?
- Proximal - Distal (shoulder -> digits)
- Cranial - Caudal (Hallux -> Phalanx V)
- Dorsal - Ventral (Dorsum -> Palm)
Apical Ectodermal Ridge
- Specialized, multilayered epithelial structure located along the ridge of each limb
What induces the AER?
FGF10 (produced by the mesodermal band)
Limb consists of:
- Mesoderm/mesenchyme core
- AER at top of limb bud
What does AER secrete?
FGF8
___ feedback loop between FGF8 and FGF10
Positive
What type of signaling is essential for the initiation of limb development and regulates the outgrowth of the proximodistal axis?
FGF
Complete/early removal of AER (or FGF8) results in:
Arrested limb development (if removed early enough then limb will be completely absent)
Removal of AER (of FGF8) at later stages results in:
Loss of more distal elemtents
Transplanting an AER (or adding FGF8) can result in:
Supernumerary limbs (new limb bud/extra limbs)
List the 8 Limb Anomalies
- Meromelia
- Amelia
- Phocomelia
- Adactyly
- Ectrodactyly
- Polydactyly
- Brachydactyly
- Syndactyly
Meromelia
- Absence of part of a limb
- Intermediate to late loss of FGF (protein) signaling
Amelia
- Absence of entire limb
- Early loss of FGF signaling
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 thalidomide exposure during prenatal development
Adactyly
- Absence of digits
- Late loss of FGF signaling
Ectrodactyly
- Split hand or split foot anomaly
- “Lobster claw” deformity
- Partial absence of FGF8 from AER
Cranial-caudal axis is patterned by the:
Zone of Polarizing Activity
SHH patterning across digits
- Digit 1: SHH independent
- Digit 2: Paracrine SHH signaling (concentration and diffusion)
- Digit 3: Autocrine/paracrine SHH signaling (time of expression and concentration)
- Digits 4 & 5: Autocrine SHH signaling (time of expression)
Where is the ZPA located?
At the caudal base of the limb bud near future digit 5
What regulates the cranial-caudal axis?
SHH signaling from ZPA
What signaling molecule is expressed in the ZPA and is sufficient to provide ZPA function?
SHH
What happens if ZPA is grafted to cranial limb bud mesoderm (implant SHH producing fibroblasts into the anterior portion of the limb bud)?
Duplicated (mirrored) digits emerge
What happens if there is an over-expression of SHH in limb development?
Polydactyly because it establishes a second Zone of polarizing activity and thus more digits than normal
What gene regulates the cranial-caudal and proximodistal axes?
Hox genes
What Hox genes are expressed within the scapula?
Hox9
What Hox genes are expressed within the arm (humerus)?
Hox9 & Hox10
What Hox genes are expressed within the ulna, radius, and proximal carpals?
Hox9, Hox10, & Hox 11
What Hox genes are expressed within the distal carpals?
Hox9, Hox10, Hox11 & Hox12
What Hox genes are expressed within the metacarpals and phalanges?
Hox9, Hox10, Hox11, Hox12 & Hox13
Hox9-10 paralogs specify:
Stylopod
Hox11 paralogs specify:
Zeugopod
Hox12-13 paralogs specify:
Autopod
Brachydactyly
- Shortening of the fingers and toes due to unusually short bones
- Genetic changes in the HOXD13 gene or PTHLH gene (parathyroid like hormone)
- Autosomal dominant inheritance
What signaling molecule is expressed in the dorsal ectoderm and is a primary regulatory of dorsal fates?
Wnt7a
Overexpression of Wnt7a results in:
Dorsalized structures
Wnt7a KO mice have ___ paws
Ventralized paws (foot pads form on dorsal surface)
What signaling molecule is expressed in the ventral ectoderm?
En1
What are the functions of En1?
- Prevents expression of Wnt7a in the ventral part of the limb
- Restricts positioning of the AER to establish the dorsal-ventral axis
Removal of interdigital mesenchyme involves?
- Apoptosis of interdigital mesenchyme which frees the digits and allows mobility
- Requires BMP signaling
If high levels of BMP signaling:
Increased cell death
If low levels of BMP signaling:
Decreased cell death (webbing of digits)
When do digital rays form in the hand plates? Foot plates?
- By the 6th week
- By the 7th week
What week of development do separate digits form?
8th week
Syndactyly
- Fusion of digits because digital rays rail to develop
- two types:
(1) Cutaneous Syndactyly: webbing between digits due to failure to degenerate cutaneous elements; disruption in BMP signaling, lack of apoptosis
(2) Osseous Syndactyly: fusion of bones (synostosis) due to failure of notches to develop between digital rays; autosomal dominant; HoxD13 mutation
Dorsal muscle mass forms:
- Extensors and supinators of upper limb
- Extensos and abductors of lower limb
Ventral muscle mass forms:
- Flexors and pronators of upper limb
- Flexors and adductors of lower limb
What arises from the somatic layer of lateral plate mesoderm?
Limb tendons
When does limb innervation begin?
5th week
What two branches does a spinal nerve branch into after exiting the spinal cord?
(1) Dorsal ramus -> Epimere
(2) Ventral ramus -. Hypomere & limbs
Do motor or sensory neurons innervate first?
Motor neurons
Muscles originating in the dorsal muscle mass are innervated by dorsal branches of the:
Ventral Rami
Muscles originating in the ventral muscle mass are innervated by ventral branches of the:
Ventral Rami
