Msk Embryology II

Question 1

interzone

Answer 1

an undifferentiated mass of mesenchyme separating adjacent masses of hyaline cartilage; the beginning of the formation of joints

Question 2

Transforming Growth Factor Beta (TGF-b) and formation of joints with large ROM

Answer 2

• is the regulatory compound required for the interzone to differentiate into synovial joints
• mesenchyme of the interzone will differentiate into different connective tissues depending on what regulatory compound goes to it.
• for joints with large ROM (diarthroses), movement of the joint is required for normal joint development

Question 3

Arthrogryposis

Answer 3

• congenital defect
• caused by muscle defect that results in greatly reduced/absent joint movements
• through external factors that impede joint mvmt can also produce it
• joint immobility causes a build up of fibrous tissue within the joint causing distorting contracture

Question 4

4 factors that are necessary for proper development of skeletal muscle

Answer 4

• mesenchymal cells from which all muscle cells differentiate; skeletal muscle from axial mesenchyme
• proper genetic signaling to control proliferation, migration, and differentiation of the mesenchyme
• an exisiting connective tissue framework (muscle grows into tendon)
• fetal movements; contraction of the muscle and “normal” joint movements are necessary

Question 5

Poland Syndrome

Answer 5

• condition characterized by the unilateral absence of pec major and the anterior axillary fold
• best understood as disruption of the underlying connective tissue framework since adjacent connective tissue is also disrupted
• cause unknown, may reflect disruption of the apical extodermal ridge or vascular supply

Question 6

Molecular biology of skeletal muscle

Answer 6

1. mesenchyme differentiates into myogenic cells
2. exposure to Fibroblast Growth Factor (FGF) and TGF-b the myogenic cells undergo rapid mitotic proliferation
   
   • if undifferentiated, termed satellite cells and are important for muscle tissue repair
3. transcription factor MyoD stops mitotic division and activates muscle-specific gene expression; myogenic cells bound to MyoD are termed post-mitotic myoblast
4. myoblasts fuse to form myotube, a multinucleated synctium; myotube synsthesizes the contractile proteins (actin, myosin, troponin, and tropomyosin) as well as scaffolding proteins (Dystrophin, Titin, Nebulin, and Myomesin)
5. once synthesized, myotube is now a muscle fiber

Question 7

What is the pattern of muscle differentiation starting with the myotome and including the spinal nerves?

Answer 7

• the myotome (part of the differentiated portion of each somite) differentiates into a dorsal epimere and a ventral hypomere that migrate apart from each other
• epaxial muscle is formed from the epimere that ends up dorsal to the vertebral transverse process and teh spinal nerve
• hypaxial muscle is formed from the hypomere on the ventral plane of the transverse process and spinal nerves
  
  • non-axial muscle of the body is derived from the hypomere
• as the spinal nerve extends laterally, it reaches the dividing myotome and separates into dorsal ramus and ventral ramus

Question 8

What is the Lateral Somatic Fronteir

Answer 8

• border between the somite and the lateral plate mesoderm (passing through intermediate mesoderm)
• used to divide the embryo into a medial primaxial domain which will contain only somatic-derived mesoderm and abaxial domain which will contain mesoderm derived from both the somite and the partial lateral plate mesoderm

Question 9

Differentiate between primaxial domain and abaxial domain.

Answer 9

• separated by the lateral somitic fronteir
• abaxial domain
  
  • myogenic cells from hypomere
  • induced by lateral plate mesoderm
  • innervated by ventral ramus
  • connective tissue from lateral plate
  • body wall and appendicular muscles
• primaxial domain
  
  • myogenic cells from epimere and hypomere
  • induced by neural tube and notochord
  • innervated by dorsal and ventral ramus
  • connective tissue from somite
  • epaxial and hypaxial muscles

Question 10

Briefly discuss the development of muscles in the head through 3 patterns and why neural crest cell derived musculature is different

Answer 10

• all from somitomeres

1. skeletal muscle of the tongue migrates into the developing tongue similar to the appendicular muscles
2. extraocular muscles form in 3 of the somitomeres and then migrate into the orbit as condensations
3. branchial muscles form through early interaction with neural crest cells - precedes the development of the phyrngeal (branchial) arches

• muscles derived from NCC have contractile proteins that are molecularly distinct from the other skeletal muscle in the body

Question 11

Muscular Dystrophy

Answer 11

• over 30 different kinds of genetic disorder
• characterized by disruption of normal skeletal muscle function
• most common is Duchenne Muscular Dystrophy
• caused by X linked gene(DMD) (male occurence) involved with the scaffolding protein Dystrophin
• normally detected due to problems learning to walk, marked by steady progression of muscle wasting, then typically death in the late teens or early 20s.
• milder form delays onset 15-20 years Becker Muscular Dystrophy

Question 12

What genes specify the location of the forelimb and hindlimb? When does limb development begin?

Answer 12

• Hox genes create morphogenic fields along the cranio-caudal axis of the embryo
  
  • they specify the future location of the forelimb (somites C5-C8) and hindlimb (somites L3-L5)
• Limb development begins in week 4; development of forelimb precedes hindlimb by 2-5 days

Question 13

Limb bud

Answer 13

• initial representation of the limb
• block of proliferating mesenchyme derived from parietal plate mesoderm
• limb bud mesenchyme has both limb identity and polarity independent of the other limbs and the rest of the embryo

Question 14

When is the critical period for limb development and what are the major causes of major limb defects?

Answer 14

• critical time: 24-36 days after fertilization
• most caused by genetics, teratogens, and physical factors

Question 15

How is anterior/posterior polarity of the limb bud determined?

Answer 15

• determined by a group of cells termed the Zone of Polarizing Activity (ZPA)
  
  • located on the posterior margin of the limb bud
• ZPA mesenchymal cells produce Retinoic Acid and Sonic Hedgehog (SHH) both of which establish morphogenic fields

Question 16

What is “Mirror Hand”?

Answer 16

• defect or disruption in ZPA causing all of the fingers to look the same and frequently the occurence of extra fingers (polydactyly)

Question 17

How is the proximal/distal axis of the developing limb established?

Answer 17

• established by a thickening of the ectoderm over the distal tip of the limb bud, the Apical Ectodermal Ridge (AER)
  
  • ​cells of AER create a morphogenic field of FGF which stimulates mitotic proliferation of the mesenchyme
  • FGF creates a group of mesenchyme cells just deep to the AER called the Progress Zone
    
    • cells here proliferate, but do not differentiate
    • limb elongation occurs here
  • in the layer of cells deep to the Progress Zone, FGF is less, and cells divide more slowly and differentiate
• limb develops proximally to distally

Question 18

Truncated Limb Syndrome

Answer 18

• disruption of AER, either physcially or through vascular anomaly, producing a complete proximal limb then an abrupt termination of the limb distally

Question 19

How are hands and feet formed from mesenchyme?

Answer 19

• differential growth in the Progress Zone results in the distal end of the limb being flattened and paddle shaped, the Hand or foot plate
• day 48, AER breaks up into 5 distinct ridges
• apoptosis will remove cells between the 5 ridges to form the digits

Question 20

What can occur with abnormal subdivision of the AER? What can occur with abnormal apoptotic clearing?

Answer 20

• polydactyly
• Cleft Hand or Foot Syndrome (missing middle digit with marked gap between remaining digits)
• syndactyly (fusion between digits)
  
  • Cutaneous syndactyly - soft tissue webbing
  • Osseous Syndactyly - fused bony elements

Question 21

Where does limb musculature come from?

Answer 21

• mesenchyme from the parietal lateral plate forms the appendicular skeleton and all the connective tissue framework for the muscles
• mesenchymal cells that will form the appendicular muscles migrate into the limb bud from the hypomere (from the somite) during week 5

Question 22

What are the 3 phases of development of appendicular muscles?

Answer 22

1. cells migrate from the hypomere into one large mass in the proximal base of the limb bud, within this mass the cells retain a somite-specific pattern of organization
2. cells migrate further into the limb bud and divide into two large groups
   
   1. flexor condensation
   2. extensor condensation
      
      • cells within each condensation no longer have a somite-specific arrangement
3. the two condesations subdivide into muscle-specific groups of cells; cells within each muscle can come froma variety of somites

Question 23

What are the two molecular cues that are most important in the formation of the limb muscles?

Answer 23

• C-Met receptor tyrosine kinase - controls the movement of the developing muscle cells into the limb bud
• Myogenic Determination Factors (MyoD) - controls the muscle-specific differentiation

Question 24

Discuss the innervation of the limbs.

Answer 24

• ventral rami of spinal nerves extend into the limb bud after the developing muscle cells have formed into flexor and extensor condensations
• in the limb bud, ventral ramus divides into two branches, one to each condensation
• as individual muscles differentiate from condensation, many nerve branches will combine so that a single muscle can be innervated by multiple levels of spinal nerves
• sequence results in a neural plexus forming at both the forelimb (brachial plexus) and hindlimb (lumbosacral plexus)

Question 25

Discuss how limbs find the correct rotation and when.

Answer 25

* Day 47, limbs undergo long-axis rotation * forelimbs rotate laterally * hindlimbs rotate medially * both of them rotating 90 degrees * combined differential rotation of 180 degrees leaves the limbs with opposite polarity * largest digit on opposite sides, flexion of the limbs in opposite directions

Question 26

Discuss sensory innervation of the limbs.

Answer 26

* follow the pattern of the motor axons to invade the limb bud * contact receptors in the skin **before the rotation of the limbs** * combination of patterning after the motor axons but before limb rotation means that bothe the spinal-specific pattern (**Dermatome)** and the nerve- specific (**cutaneous specific)** pattern are "distorted" or non-parallel and discontinuous

Question 27

Talipes equinovarus

Answer 27

* clubfoot * most common musculoskeletal defect * torsion at the ankle renders the plantar surface of the foot non-weight bearing * no underlying anatomical defects, therapeutic adjustment is all that is required for normal posture