Lecture 14: Musculoskeletal Development I

Question 1

Describe the mesenchymal origin of each major part of the skeleton

Answer 1

Mesodermal sclerotomes: Vertebral column, Ribs, Sternum

Lateral plate mesoderm: Limb bones, Girdles

Head mesoderm: Calvaria and base of skull

Neural crest: Facial bones

Question 2

Common differentiation pathway

Answer 2

• Mesenchyme is induced to enter the common pathway
• Production of N-cadherins which promote mesenchymal cell condensation
• TGF-b stimulates synthesis of fibronectin and N-CAM
• Aggregated state of mesenchymal cells is stabilized

Question 3

Membranous Bone Differentiation Pathway

Answer 3

• Requires transcription factors Runx-2 and Osx
• Mesenchymal cells differentiate into osteoblasts

Question 4

Permanent Cartilage Differentiation Pathway

Answer 4

• Mesenchymal condensation forms chondroblasts
• Sox-9 causes chondroblasts to secrete collagen II and cartilage matrix
• Sox-9 is continually expressed in permanent cartilage

Question 5

Endochondral Bone Differential Pathway

Answer 5

• Runx-2, ihh, and BMP-6 induce this cartilage to undergo hypertrophy
• Hypertrophic cartilage cells secrete bone proteins and vascular endothelial growth factor
• Invading blood vessels erode the hypertrophic cartilage and bring in osteoblasts to replace cartilage with bone

Question 6

Describe the origin of each part of the vertebra… centrum, neural arches, and costal processes and ribs

Answer 6

Centrum: derived from ventral and medial parts of paired sclerotomes

Neural arches: arise from dorsal regions of sclerotomes

Costal processes/ribs:

• Proximal development depends on expression of myotomic myogenic factors Myf-5 and Myf-6
• Distal development depends on BMP signals from somatopleural mesoderm

Question 7

Differentiate Hox gene boundaries for the different regions of the vertebral column

Answer 7

Hox 3: occipital-cervical boundary

Hox 6: cervial-thoracic boundary

Hox 9: attached-floating ribs boundary

Question 8

Describe results of experiments involving Hox gene knockouts

Answer 8

Single Hox gene knockouts: only minor morphological effects occur

Knockout of all Hox 10 paralogues: ribs form on all the lumbar and sacral vertebrae, Hox10 represses the influence of the anterior Hox genes

Knockout of all Hox 11 paralogues: sacrum will not form, Hox11 supresses the influence of Hox10

Mutation of a single Hox gene: only produces a minor anatomical defect, where the nonfunction of an entire group produces major effects

Question 9

Describe the development of the axis/atlas complex and identify the primordia

Answer 9

In normal development, cells from a proatlas anlage contribute to the formation of the basioccipital bone and the dens of the axis. The normal atlas forms from an anterior arch instead of the centrum. The cells that would normally form the centrum at the level of the atlas instead fuse with the axis to form the dens of the axis

Question 10

What is the relationship of Hox gene expression and the development of the vertebral column?

Answer 10

Expression of the Hox genes begins with the first appearance of the presomitic meso- derm and for most genes persists until chondrification begins in the primordia of the vertebrae. Formation of the normal segmental pattern along the craniocaudal axis of the vertebral column is ensured by the fact that most vertebrae are specified by a unique combination of Hox genes.

Question 11

How does retinoic acid affect the expression of the Hox genes and the development of the vertebral column?

Answer 11

Causes shifts in cranial or caudal levels in the overall segmental organization of the vertebrae if applied at specific developmental periods. Also known as Vitamin A

Question 12

What are homeotic transformations?

Answer 12

They represent a large shift in homeotic mutants

For example…

If RA is administered early, it results in a cranial shift (the last cervical vertebra is transformed into the first thoracic vertebra)

If RA is administered late, it causes a caudal shift (thoracic vertebrae extend into the levels of the first two lumbar vertebrae)

Question 13

Describe the origin of the sternum

Answer 13

• From lateral plate mesoderm
• Arises as a pair of cartilaginous bands
• Fused cartilaginous bands secondarily subdivide into craniocaudal elements

Question 14

Describe the origin of the clavicle

Answer 14

• Arises from neural crest
• Follows intramembranous pathway
• One of the first bones to become ossified

Question 15

What is cleiodcranial dysplasia?

Answer 15

The absence of clavicles in individuals with mutants in Runx-2

(Runx-2 is required for the differentiation of osteoblasts)

Question 16

Describe the subdivisions of the developing skull

Answer 16

Neurocranium: part of skull that surrounds the brain

Viscerocranium: surrounds oral cavity and pharynx

Occipital sclerotomes: form occipital bone

Question 17

Describe the generalized neurocranium/chondrochranium

Answer 17

• Has a cartilaginous portion and membranous portion
• Base is formed from the chondrocranium, which contains origin of occipital, sphenoid, ethmoid, and part of temporals
• Membranous part contains origin of occipital, frontals, part of temporals

Question 18

Describe the generalized viscerocranium and the bones that develop from the viscerocranium

Answer 18

• Cartilaginous portion forms:
  
  • Pharyngeal arch I (Merkle’s cartilage, malleus, incus)
  • Pharyngeal arch II (Reichert’s cartilage, stapes, styloid)
• Membranous portion forms:
  
  • Part of temporal, zygomatic, maxillary, nasal, lacrimal, palatine, vomer, pterygoid plates, mandible, tympanic ring
• Mostly comprised of the brachial (pharyngeal) arches
• The mesenchyme forms the viscerocranium is mostly from the neural crest

Question 19

What are the 4 components of a pharyngeal arch?

Answer 19

skeletal element, muscles, branch of a cranial nerve, artery

Question 20

Describe the origin of the various endochondral skull bones

Answer 20

Chondrocranium: occipital, sphenoid, ethmoid, petrous and mastoid part of temporal

Membranous Neurocranium: interparietal part of occipital, parietal, frontal, squamous part of temporal

Cartilaginous Viscerocranium: pharyngeal arches I & II

Membranous Viscerocranium: maxillary and mandible processes

Question 21

Define fontanelle and describe the pathway leading to the closure of fontanelles

Answer 21

fontanelle = broad area of connective tissue that intersects the sutures of two or more bones

BMP stimulates widespread bone formation, but the BMP antagonist, noggin, is expressed in all embryonic sutures. Under the influence of FGF-2, noggin is downregulated in the sutures that fuse, allowing BMP-mediated bone formation to cement the two adjacent skull bones.

Conversely, the absence of local FGF-2 allows noggin to repress BMP in the sutures that are destined not to fuse.