Embryology of the Spine and Limbs
Early Differentiation: Trilaminar germ disk is formed during gastrulation: Primitive Streak forms along the caudal midline of the bilaminar disc Þ epiblast ingresses along the primitive streak displacing hypoblast, forming the endoderm and filling the space between, forming the mesoderm Þ a tube of mesoderm from the primitive pit extends cranially to form the notochord.
begins: The notochord induces epiblast cells (now called Ectoderm) to form a neural plate
Þ hard and soft tissue of head and neck
Neural plate folds into hollow neural tube Þ Cranial/caudal zipping: happens quickly under chemical cues; folic acid plays important role in maintaining this process. Spinabifida results from mal-closure which can occur in varying degrees:
- Morphogens (chemical cues) = TGFß, activin, Retinoic Acid, FGF (triggered by HOX genes), some neurotransmitters.
- Neural plate lateral margins elevate to form ridges = Neural crest cells (Ectomesenchyme)
Þ potential exposure of spinal cord. This occurs frequently in sacral region but also lumbar.
Spinabifida Menigocele: the dura and arachnoid protrude as a CSF containing sack beyond the skin of the back.
Meningiomyelocele: spinal cord is actually on the outside of body
Meningomyeloschisis complete non-closure and differentiation of neural tube. Not always fatal but clinical nightmare
Day 25: Cranial neuropore closes. Day 27: Caudal neuropore closes and primitive streak disappears.
- Spinabifida occulta: bony closure of most of the tube but open in the back = lack of midline fusing on the dorsal side of vertebra
Þ Somitomeres Þ Somites in occipital to caudal region (wk 3-4)
(2) Intermediate Mesoderm – forms the nephrogenic cord and gonads
(3) Lateral mesoderm Þ parietal and splancnic mesoderm
Somites form the primary longitudinal segmentation of the embryo (8 cervical, 12 thoracic, 5 lumbar, 5 sacral, 8-10 coccygeal)
Somites differentiate into:
- Mesoderm lateral to the notochord forms:
Dermomyotomes differentiate into
- (1) sclerotomes (hard segment)
- (2) dermomyotomes (skin-muscle segment)
Week 4: Sclerotomes grow differentially to surround the notochord and neural tube.
- (1) dermotomes (forms dermis-mesodermal contribution to skin)
- (2) myotomes (forms muscles)
Þ caudal ˝ of each sclerotome fuses with cranial ˝ of succeeding one (error Þ hemi vertebra = vertebra with discontinuous mass)
these fusings Þ precartilagenous vertebral bodies: this is why vertebrae are intersegmental -come from diff. somites
mesenchymal cells fill the space created by this fusing Þ intervertebral discs
notochord degenerates except in middle of disc = nucleus pulposis; circular cells form outer disc = annulus fibrosis
nerves are associated with each myotome therefore are segmental; arteries are intersegmental (associated with >1 somite)
costal processes appear on the vertebral bodies
- concurrently, sclerotomes split
Þ deep back muscles
hypomere (large ventral component innervated by ventral primary rami)
in trunk these nerves retain original segmental character
mesodermal sternal bars appear (ribs)
Week 6: Costovertebral joints begin to develop, ribs connect with sternal bars Þ begin to fuse (error here Þ open sternum)
- thoracic costal processes elongate to form ribs
- myotomes separate into:
- epimere (small dorsal component innervated by primary dorsal ramus)
Note: The vertebral column grows faster than the spinal cord, so the inferior tip of the spinal cord (Conus Medularis), which starts by the coccygeal region in the fetus, ends up 8 (5sacral+3 Lumbar) vertebrae higher in the adult, around L1-L2 junction. The conus Medularis gives rise distally to the Cauda equina = the roots of the upper sacral nerves that extend beyond the termination of the spinal cord at the first lumbar vertebra in the form of a bundle of filaments within the vertebral canal resembling a horse's tail.
the dura mater (outer most layer of the meninges) and arachnoid layer end at S2. The pia mater (adherent to spinal cord) becomes the filium terminale after the conus medularis.
Curvature of the Spine: Kyphosis: the curvature of the spine that is convex posteriorly. This is the original fetal curvature. Near birth and into childhood and beyond cervical and sacral Lordosis develops which is convex curvature posteriorly. This is a consequence of walking on 2 legs so that our trunk can support itself on 2 limbs.
- vertebral chondrification centers develop-centra, arches and processes:
- centra fuse in 3-5 yrs; centra and arches fuse in 3-6 yrs. Secondary centers of ossification = apices of transverse and spinous process and annular epiphysis (inferior and superior rim on circumference of body)
- epimere gives rise to spinal musculature, hypomere gives rise to trunk wall muscles; each pulls nerves along.
- vertebral disc distinct; Sacral vertebrae fuse to form sacrum
Upper Limb – Review basic anatomy: in the upper limb pectoral girdle attached to the trunk. Free limb hangs from side. Major proximal bone = humerus Þ two forearm bones radius and ulna, Þ wrist (mass of bones) =carpusÞ tubular bones =(Metacarpus Þ 2-3 Phalanges)
Lower Limb – pelvic girdle. Major proximal bone = femurÞ 2 calve bonesÞ tarsusÞ tubular bones = (Metatarsals Þ Phalanges 2-3
Week 4: Ectodermal encased mesenchymal cells(from posterior to Henson’s Node) begin to form limb buds.
- Vessels: follow major bones, single proximal vessel that splits at point radius and ulna arise.
Þ muscle and cartilage
the AER maintains the distal proximal gradient and differentiation with FGF;
On the post axial (caudal) side there is the Zone of Polarizing Activity (ZPA) which is also stimulated by AER.
- thickening of apical ectoderm, called the Apical Epidermal Ridge (AER), is induced by the underlying mesenchyme
- AER reciprocally maintains the cell immediately deep to AER = Progress Zone (PZ)
- farther cells differentiate
Cells from myotome begin to migrate into limbs, the respective innervation follows.
Week 6 -distal differentiation: skin in-between the rays is subject to programmed cell death (PCD) which allows the separation of different limbs. Failures here results in differing degrees of syndactyly from lack of paddle differentiation to lack of separation of adjacent fingers (programmed cell death). Can happen in hands or feet.
- the ZPA maintains the medial lateral (cranial caudal) organization of the fingers with sonic hedge hog
- Dorsal/ventral is maintained by Wnt
Week 7 –upper/lower differentiation identifiable: lower 2 days advanced
- Shortened limbs or Amelia (no limb). Extra digits, cleft hand or foot.
- these result from disruption of gradients mechanically or through drugs (Thalidomide) resulting in problems with AER or ZPA.
- mesenchymal cells from within the limb condense into hyaline cartilage models (eventually replaced by bone)
- formation of hand and foot paddles.
Beyond Week 7:
joints arise from dense inter zonal mesenchymal clefts because prospective bones form in a trilaminar layer.
Capsule derives from perichondrium; inner layer of capsule Þ synovial membrane = lubricant forming sheet
Primary ossification centers are present in the diaphysis (shafts) of all long bones by week 12
- upper rotates laterally (extensor dorsal, thumb lateral) lower rotates medially (extensor ventral, big toe medial)
- Migrating myotomal cells condense in limb bud to form extensor (dorsal, elevator) and flexor (ventral, depressor) muscle mass
- Segmental spinal nerves (ventral primary rami VPR) adjacent to limb buds (upper = C4-T2; lower= L2-S2) penetrate mesenchyme.
- VPR anterior division innervates the preaxial (cranial) flexor muscles; posterior VPR innervates postaxial (caudal) extensors
- Nerve attachment to differentiating myotomal blocks maintains the vitality of both muscle and nerve.
- Skin covering limb is also segmentally derived which is reflected by dermatomes, which correspond to derived segment
Secondary ossification centers are ( epiphysis and apophysis) are separate foci of bone formation that later fuse with diaphysis
completed by year 25
- this bone formation replaces the cartilage model and is completed by year 20.
Meromelia: partial absence of limbs; Micromelia: all segments short
Syndactyly: fusion of digits; Polydactyly: extra digits
Cleft hand (lobster claw deformity); Club foot: inverted, adducted and planar
Achondroplasia: systemic disruption of endochondral ossification Þ dwarfism