Spine, Muscle and Limb Development Flashcards
What are the precursors for: Smooth muscle Cardiac muscle Skeletal muscle
Smooth - Splanchnic mesoderm and local mesenchyme
Cardiac - Splanchnic mesoderm
Skeletal - Paraxial mesoderm
What are the three types of muscle tissue?
Smooth Cardiac Skeletal
What is intraembryonic mesoderm divided into?
Pariaxial mesoderm
Intermediate mesoderm
Lateral mesoderm
Which mesoderm forms somites?
Paraxial mesoderm
What is a somite?
Temporary structure in embryo allowing embryo to segregate certain precursor structures that eventually become skeletal muscle and bone
Two types of tissue in the embryo
Epithelium and mesenchyme
How does mesenchyme become somite?
Mesenchymal to epithelium transformation causes a structure with an outer surface of epithelium and inner portion of mesenchyme
What is the outer epithelial surface of somites called
Dermomyotome
What causes differentiation of the dermomyotome
Signals from surrounding tissues (notochord, neural tube and BMPs)
What is the lateral somite frontier
The boundary between different sets of signals sent to the somite
What is the primaxial domain?
Forms muscles that attache to scleratome derived bones (vertebrae)
What is the abaxial domain
Forms muscles of ventrolateral abdominal wall and limbs
What do the dermomyotomes form after they are differentiated?
Myogenic cells, which then become myoblasts
How is skeletal muscle formed from myoblasts?
Signals from other cells cause myoblasts to fuse together into myotubules which then join to form skeletal muscle cells
Why does skeletal muscle have multiple nuclei
Because it is formed from multiple myoblasts
The central region of the dermomyotome forms…
Satellite cells - precursors to skeletal muscle cells (muscle stem cells)
What are the master regulators for skeletal muscle formation?
Myo-D family of genes: Myf-5 Myogenin MRF-4 PAX-3 PAX-7
How do myotubes differentiate into different types of muscles (proposed strategies)?
Change in muscle fiber direction (abdominal muscles) Tangential splitting into layers Fusion of adjacent myotomes (for large muscles)
How do skeletal muscles become innervated
- Innervated early as pre-muscle masses - Some pre-muscle masses take their innervation with them as they migrate - Spinal nerves innervate somite derived skeletal muscles of trunk and limbs
What does myotome mean structurally?
All of the muscles that come from a single pair of dermomyotomes (which have the same innervation)
What innervates myotomes?
Branches of primary Rami of Spinal nerves
What are the muscles innervated by dorsal primary rami?
Epaxial muscles (above the axis) - Back muscles
What muscles are innervated by the ventral primary rami?
Hypaxial muscles (below the axis) - abdominal muscles
How many weeks does it take for all muscle groups to have formed
8 weeks
What is abnormal skeletal muscular development
Absence of a muscle or part of a muscle
What is missing in Poland syndrome
Pectoralis major
What is missing in Prune Belly syndrome
Abdominal muscles
What is congenital toricollis
Missing sternocleidomastoid
What is the most common congenital muscle problem?
Muscular dystrophy
Myoblasts from the _________ dermomyotome form primaxial domain muscles
dorsomedial
Myoblasts from the ___________ dermomyotome form abaxial muscles
dorsolateral
What two tissues make up the skeleton?
Bone and cartilage
What embryonic progenitor tissues are used to form skeletal tissues?
Mesenchyme
In the trunk, mesenchyme is derived from…
Paraxial mesoderm
Somatic mesoderm
In the head, mesenchyme is derived from…
Neural crest ectomesenchyme Head mesoderm
What is STFM
Skeletal Tissue forming mesenchyme
What are some of the shared features of STFM development?
- Often skeletal progenitor cells migrate or are displaced from their site of origin
- STFM condenses into pre-skeletal condensations
What influences STFM differentiation?
- Epithelial-mesenchymal interactions
- Specific transcription factors
- Other signaling molecules
What is the osteoblast-specific transcription faster gene (bone master gene)
RUNX2a (CBFA1)
What is the chondroblast specific transcription factor
Sox 9
What is the first step in the primary differentiation pathways of STFM?
The initial step is a condensation of pre-skeletal mesenchyme (influenced by signals from adjacent epithelium)
What transcription factors are involved in endochondrial ossification?
Sox-9 Ihh; VEGF RUNX-2
What transcription factor is involved in intramembranous ossification?
Runx-2
What is the ossification center?
The area of bone where ossification begins
Where are locations for the primary center of ossification?
The initial center to appear
- Shaft of long bone
- Center of flat bone
First appears at 7 weeks of development
When would you see secondary ossification centers?
Where would you see secondary ossification center?
Appear in perinatal, postnatal or postpuberal period Ends of long bones (epiphysis), heads of ribs
When does the secondary ossification center close?
20s -30s and controlled by hormones
Why are there spaces between the long bones of the limbs as seen on the X-ray of a newborn?
Those spaces are still cartilage
What is Bone Age?
The amount of Epiphyseal cartilage retained - Comparison of bone and chronological ages is a measure of skeletal growth and maturation
Generalized Skeletal Tissue Dysplasias
May affect all or part of the skeleton:
- Often affect growth and may result in short or tall stature
- Often a component of the ECM, causing it to be defective
- Often there is a recognized genetic component
Marfan’s syndrome
Alteration of Fibrillin production
Mucopolysaccharidoses
Defect in synthesis, storage and transport of a particular lysosomal enzyme - results in accumulation of substrate (lysosomal storage diseases)
Altered hormone secretion can affect skeletal growth. What happens in
Growth Hormone (Increases)
Growth Hormone (Decreases)
Thyroid Hormone (Decreases
Growth hormone Increased: Lead to Gigantism
Growth Hormone Decrease: Lead to Pituitary Infantilism (Dwarfism)
Thyroid hormone Decrease: Lead to Cretinism (mental deficits included)
Which disease results from a mutation in the gene encoding fibroblast growth factor receptor 3 (FGFR3)?
Achondroplasia
What is the abnormality seen in achondroplasia?
Failure of endochondral ossification
What lower extremity deformity is seen in achondroplasia?
Genu varum (bowlegs)
What cell functions abnormally in osteopetrosis?
Osteoclasts
How would you treat osteopetrosis?
Bone marrow transplant
What are the two parts of a skeleton?
Axial and appendicular
What’s the genetic abnormality in osteogenesis imperfecta?
Type 1 collagen
What types of bones are formed by:
- Paraxial mesoderm
- Somatic mesoderm
Paraxial mesoderm: vertebral column and ribs Somatic mesoderm: sternum and limb skeleton
Which signal causes the medial and inferior portions of the somite to become mesenchymal cells?
Sonic the hedgehog
What is the scleratome?
Precursor to the vertebrae formed from portions of the somites
Scleratome tissue organizes into _____ and _______ subdivisions
Cranial; caudal
What is resegmentation of Scleratome tissue?
The process by which the two subdivisions of the scleratome separate from each other due to the spinal nerve cutting across them
- The cranial portion of one scleratome fuses with the caudal portion of an adjacent scleratome
- Myotome does not separate with the scleratome and ends up linking pairs of vertebrae
Subdomains of scleratome tissue:
Central:
Ventral:
Dorsal:
Lateral:
Somitocoel cells:
Central: Pedicle, proximal ribs
Ventral: Vertebral body, IV disc
Dorsal: Dorsal part of neural arch, spine
Lateral: Distal rib
Somitocoel cells: Vertebral joints, IV disc, proximal ribs
Cells from the cranial half of the scleratome contribute to:
Vertebral body, small parts of neural arch and distal rib (in thoracic region
Cells from the caudal half of the scleratome contribute to:
Vertebral body, transverse process, most of neural arch and proximal part and main part of distal rib (in thoracic region)
Cells at intersegmental boundary and somatocoel cells (of the scleratome) form:
The intervertebral disc
Patterning of vertebrae is determined by:
Homeobox genes (Hox genes)
What happens to the costal process in the thoracic region?
Extends laterally and becomes a rib
Closure of the neurocentral junction (primary growth center of vertebrae) occurs at what age?
3 - 6 years old
What is the klippel-fiel sequence?
Fusion of cervical vertebrae
- Number of cervical bodies is less than normal.
Dysraphism
Open Vetebral Column
Due to failure of fusion of the Nueral arches of the A SINGLE vertebra process.
Rachischisis
Many or all vertebrae have unfused spinous processes
Extensive opening of vertebral column with CNS involvement
Spina Bifida
Variation in length of opening of vertebral column
- lack of formation of spinous processes
- Only a few vertibrae are unfused
Defects Resulting in assymetry
Congenital kyphosis
Congenital lordosis
Congenital scoliosis
Two causes of congenital scoliosis
Failure of segmentation
Failure of formation
Describe the formation of the sternum
Sternal bands fuse together to form cartilage sternum; ossification centers lead to an ossified sternum
- Sternum is the location of the first ossification centers in development
Abnormal development of ribs can lead to…
- Extra ribs
- Abnormal ribs (fused or forked)
- Clefts
- Pectus Excavatum (hollow)
- Pectus carinatum (keel shaped)
What is the basic organizational plan of tissues in the adult limb?
Consist of:
- Skeletal elements
- Skeletal muscles
- Fibrous connective tissue
- Neurovascular Structures
- Skin
Limb Precursor tissues
Limb mesenchyme (somatic mesoderm and somitic mesoderm)
Surface ectoderm
Development of the upper limb is ahead of that in the lower limb by about __ - __ days
1-2
Step 1 of the limb development
Establishment of the limb field
- Bilateral areas of somatic mesoderm induced by gene expression
What is the area between the limb fields called?
Flank region
Step 2 of Limb development
Budding (appearance)
- Located at specific axial levels
- Budding is an inherent property of mesoderm
What is the name of the thickening that appears at the dorsal/ventral surface interface?
Apical Ectodermal Ridge (AER)
Step 3 of limb development
Elongation of the limb
- Segments appear along a proximal-distal axis
- Elongation results from epithelial-mesenchymal intearactions at AER/mesoderm interaface
Step 4 of limb development (week 5)
Tissue formation and organization
- Differentiation occurs in proximal-distal direciton
- Somatic mesoderm condenses to form cartilage
- Somite derived myoblasts migrate into limb to form skeletal muscles
- Nerves and vascular precursors migrate into limb
What are the three linear axes upon which limb development occurs?
Proximal-Distal: Elongation, segment formation
Anterior-Posterior: Cranial-caudal/Preaxial-postaxial borders, digit development
Dorsal-Ventral: Compartments - muscles and neurovascular structures
What allows a bud to become a 3 part limb?
Reciprocal signaling
- Mesenchyme produces Fgf10 which goes to ectoderm which responds by producing Fgf8 (Fgf8 produces the AER)
- Retinoic acid - stronger proximally and weaker distally
- Fgf and Wnt - stronger distally and weaker proximally
Role of Mesenchyme in limb development
Induces the AER (Fgf10)
Sustains AER (Fgf10)
Determines limb type (upper or lower)
AER role in limb development
- Maintains a proliferating pool of mesenchyme cells for linear growth (Fgf8)
- Maintains A-P axis signaling center
- Interacts with P-D and A-P specific proteins to provide mesenchyme cells with positional information
What is the fate of the mesenchyme adjacent to the AER?
Forms segment specific skeletal elements Forms fibrous connective tissue
Removal of the AER leads to…
Limb truncation - elongation of the limb stops
How common are limb malformations?
2/1000 births (1/500)
Types of limb anomalies (7)
Failure of formation of parts
Failure of differentiation
Duplication of parts
Overgrowth of parts
Undergrowth of parts
Congenital Constrictive Band syndrome
Generalized skeletal abnormalities
Failure of communication between AER and mesenchyme can lead to…
Failure of formation of parts
What is a fibular hemimelia
Congenital absence of the fibula
- most common congenital absence of long bone extremities
What is Phocomelia? What drug can cause it?
Distal part of the extremities are attached directly to the body;
Thalidomide
What develops along the anterior-posterior axis in limb development?
Digits
What is the zone of polarizing activity (ZPA)?
A signaling center along the posterior border of the limb that controls pattern of digits
- mediated by Sonic Hedgehog (Shh)
- Retinoic acid mimics Shh
What happens if an additional ZPA signal is added?
Secondary focus of Hox gene expression - duplication of the digits
How does apoptosis play a role in limb development?
Separation of digits
Absence of distal phalanx of large digit
Failure of differentiation leads to…
Syndactyly - Two partially combined toes
Sirenomelia - Combined legs
Triphalyngeal Thumb - Three phalanges in the thumb
What type of inheritance is involved in duplication of digits?
Autosomal dominant
Mediators of Dorsal-Ventral patterning
Secreted factors: Wnt 7a
Transcription factor engrailed (En)
In the anatomical position the thumb is…
Cranial
What is developmental dysplasia of the hip?
Underdevelopment of femoral head or hip socket and general joint laxity
More common in females
Cleidocranial Dysplasia
Missing clavicle and facial anomalies
What is talipes equinovarus?
Club foot - turning in of the feet
