Lecture 2 Limb Devo

Question 1

At ~ ____ weeks, initiation of limb formation begins in response to expression of ____ genes in the lateral body wall
* upper limb ____
* lower limb ____

Answer 1

At ~ 4 weeks, initiation of limb formation begins in response to expression of HOX genes in the lateral body wall
* upper limb Hox-4, -5
* lower limb Hoxc-8, -9, -10

Question 2

The critical period of limb development is 24-36 days post-fertilization (based on clinical studies of neonates exposed in utero to ____

Answer 2

The critical period of limb development is 24-36 days post-fertilization (based on clinical studies of neonates exposed in utero to thalidomide)

Question 3

Clinical connection: ____ (complete absence of one or more limbs) results from interruptions to limb bud early in development

Answer 3

Clinical connection: amelia (complete absence of one or more limbs) results from interruptions to limb bud early in development

Question 4

Apical Ectodermal Ridge (AER) regulates proximal-distal patterning of li

the AER expresses ____ which maintains cells in an ____ state
* cells in the progress zone closest to the AER proliferate which ____ the limb in a
____→ ____ manner
* forms 3 components: ____ (humerus and femur), ____(radius/ulna and
tibia/fibula), ____ (carpals, metacarpals, phalanges and tarsals, metatarsals, phalanges) in the upper and lower limbs, respectively

Answer 4

the AER expresses FGFs which maintains cells in an undifferentiated state
* cells in the progress zone closest to the AER proliferate which elongates the limb in a
proximal → distal manner
* forms 3 components: stylopod (humerus and femur), zeugopod (radius/ulna and
tibia/fibula), autopod (carpals, metacarpals, phalanges and tarsals, metatarsals, phalanges) in the upper and lower limbs, respectively

Question 5

cells farther from the AER differentiate into ____ and ____

Answer 5

cells farther from the AER differentiate into cartilage and muscle

Question 6

Clinical connection:
disruption of AER can result in ____ (absence of part of a limb; shortened limb), ____ (shortened digits), or ____ (proximal structures are intact but distal structures are partially or completely absent)

Answer 6

Clinical connection:
disruption of AER can result in meromelia (absence of part of a limb; shortened limb), brachydactyly (shortened digits), or transverse limb deficiencies (proximal structures are intact but distal structures are partially or completely absent)

Question 7

Clinical connection: ____ (congenital joint contractures) may have a neurological ( ____ neuron deficiency), muscular (myopathies, muscle agenesis), or skeletal (synostosis) cause

Answer 7

Clinical connection: arthrogryposis (congenital joint contractures) may have a neurological (**meningomyelocele, anterior horn motor **neuron deficiency), muscular (myopathies, muscle agenesis), or skeletal (synostosis) cause

Question 9

Initially, the digits are fused; at ~ day 48, apoptosis in the ____
* the AER remains intact over the digital rays ( ____induce condensation into cartilaginous models of the digital bones)
* continued apoptosis in the interdigital spaces (induced by ____) results in separation of the digits

Answer 9

Initially, the digits are fused; at ~ day 48, apoptosis in the AER separates the ridge into five parts
* the AER remains intact over the digital rays (FGFs induce condensation into cartilaginous models of the digital bones)
* continued apoptosis in the interdigital spaces (induced by BMPs) results in separation of the digits

Question 10

Clinical connection: ____ (fusion of two or more digits);

____ results from failure of the webs (mesenchyme) to degenerate between two or more digits - more frequent in foot than hand;

osseous (complex) syndactyly ____

Answer 10

Clinical connection: syndactyly (fusion of two or more digits);

**cutaneous (simple) syndactyly **results from failure of the webs (mesenchyme) to degenerate between two or more digits - more frequent in foot than hand;

osseous (complex) syndactyly (fusion of bones, synostosis) occurs when separate digital rays fail to form in the fifth week; as a result, separation of the digits does not occur

Question 11

▪ ____ cells aggregate in the ____ margin of the limb bud to form the ____
▪ ____ from the AER activates cells in the ____to express ____
SHH regulates specification of the ____
▪ as the limb elongates, the ZPA maintains its relationship with AER

Answer 11

▪ mesenchymal cells aggregate in the caudal margin of the limb bud to form the** zone of polarizing activity ( ZPA )**
▪ FGF from the AER activates cells in the ZPA to express **sonic hedgehog (SHH) ***
SHH regulates specification of the digits (e.g., thumb at preaxial border)
▪ as the limb elongates, the ZPA maintains its relationship with AER

Question 12

____ (more than five digits on the hands or feet), mirror hand or foot syndrome, can result from duplications or misexpression of ____ in ____

Answer 12

polydactyly (more than five digits on the hands or feet), mirror hand or foot syndrome, can result from duplications or misexpression of SHH in ZPA.

Question 13

▪ mesenchymal cells in the ____ of the limb bud ____ and ____ into chondrocytes and by week six form ____
▪ bone formation occurs via ____
▪ joints form in the cartilaginous condensations when chondrogenesis is
arrested (interzone); joint spaces form by cavitation in the interzone

Answer 13

▪ mesenchymal cells in the central core of the limb bud condense and differentiate into chondrocytes and by week six form hyaline cartilage models
▪ bone formation occurs via endochondral ossification
▪ joints form in the cartilaginous condensations when chondrogenesis is
arrested (interzone); joint spaces form by cavitation in the interzone

Question 14

Clinical connection: congenital absence of the radius (the radius is partially or completely absent), results from failure of the ____ to form; usually a genetic basis and often occurs as part of a syndrome (e.g., craniosynostosis-radial aplasia syndrome)

Answer 14

Clinical connection: congenital absence of the radius (the radius is partially or completely absent), results from failure of the mesenchymal primordium of the radius to form; usually a genetic basis and often occurs as part of a syndrome (e.g., craniosynostosis-radial aplasia syndrome)

Question 15

osteogenesis imperfecta results from ____ of the long bones (mutation in genes involved in production of ____

Answer 15

osteogenesis imperfecta results from hypomineralization of the long bones (mutation in genes involved in production of** type I collagen)**

Question 16

Pseudounipolar neurons in the posterior root ganglion are derived from ____

motor neurons in the anterior horn arise from ____

Answer 16

Pseudounipolar neurons in the posterior root ganglion are derived from neural crest cells

motor neurons in the anterior horn arise from neural tube