UNSW Embryology

Musculoskeletal Development - Axial Skeleton

© Dr Mark Hill (2008)

Acknowledgements

Introduction

During the 3rd week the paraxial mesoderm forms into "balls" of mesoderm paired either side of the neural groove, called somites. Different regions of the somite differentiate into dermomyotome (dermal and muscle component) and sclerotome (forms vertebral column). Vertebral bone is formed through a lengthy process involving endochondrial ossification of a cartilage formed from mesenchyme.

Cross-section of developing vertebra (longitudinal of axial skeleton).

The vertebral body begins as a bony collar that expands into regions of dying cartilage. The bony vertebral arch, enclosing the spinal cord, forms later and the arch remains open dorsally (linked by a ligament) to allow growth of the spinal cord.

The axial skeleton consists of: Skull, Auditory Ossicles, Hyoid bone, Vertebral column, Chest (sternum, ribs) The vertebral column is a series of bone segments (vertebra) separated by specialized joints (intervertebral disc). In the adult, these vertebral elements are made up of rostro-caudally: 7 cervical, 12 thoracic, 5 lumbar, 1 sacrum, coccyx. Skeletal ossification continues postnatally, through puberty until mid 20s. Abnormalities of vertebral column development can lead to defects including scoliosis (More? Scoliosis).

There are also additional notes covering molecular regulation of vertebral column development (More? Molecular - Vertebral Column).

Page Links: Introduction | Some Recent Findings | Development Overview | Somites and Sclerotome | Histology | References | WWW Links | Glossary

Some Recent Findings

Pickett EA, Olsen GS, Tallquist MD. Disruption of PDGFRalpha-initiated PI3K activation and migration of somite derivatives leads to spina bifida. Development. 2008 Feb;135(3):589-98.

"Genetic disruption of platelet-derived growth factor receptor (PDGFR) alpha results in spina bifida, but the underlying mechanism has not been identified. ...results indicate that PDGFRalpha downstream effectors, especially PI3K, are essential for cell migration of a somite-derived dorsal mesenchyme and disruption of receptor signaling in these cells leads to spina bifida."

Somites and Sclerotome

Early stage 10 human embryo showing first forming somites laterally and neural groove in the midline.

Later stage 11 human embryo showing additional somites

Somites appear bilaterally as pairs at the same time and form earliest at the cranial end (rostral, brain) of the neural groove and add sequentially at the caudal end.

Carnegie stage 13/14 Embryo Serial Section showing spinal cord (top), with sclerotome forming vertebral body (pale region below spinal cord).

Histology

Cross-section of developing vertebra (longitudinal of axial skeleton).

Centre of the image shows initial vertebra "bony collar" (in red) forming, either side of which is the original cartilage (blue) "template", outside of that again are the 2 intervertebral discs (not shown).

Reading

Human Embryology (3rd ed.) Larson Ch11 p311-339

The Developing Human: Clinically Oriented Embryology (6th ed.) Moore and Persaud Ch15,16: p405-423, 426-430

Before We Are Born (5th ed.) Moore and Persaud Ch16,17: p379-397, 399-405

Essentials of Human Embryology Larson Ch11 p207-228

Human Embryology, Fitzgerald and Fitzgerald

Human Embryology and Developmental Biology, (3rd ed.) Carlson Ch9,10: p173-193, 209-222

Computer Activities

UNSW Embryology:

• Carnegie stage 13/14 Embryo Serial Sections (Pig)
• Carnegie stage 22 Embryo Serial Sections (Human)
• Selected Carnegie stage 22 Highpower Sections (Human)
• Axial Skeleton Development
• Axial Skeleton Abnormalities - Scoliosis
• Bone Development
• Skull Development
• Systems- Carnegie stage 13/14 Embryo Serial Sections (Pig)
• Human Carnegie stages

Lectures:

These Lecture links are to current and historic courses and may also link directly to PDF version of Lecture slides (educational use only).

ANAT2300 (2004) Lecture 6 Mesoderm

ANAM1006 (2003) Musculoskel Development Lab

PDF Documents

ANAT2300 (2004) Lecture 7 Bone (view)

ANAT2300 (2004) Lecture 7 Bone (print)

Human Embryology Movies:

Fate of the Somite (315Kb)

Vertebrae (366Kb)

Embryo Images Unit:

Body Cavities, Musculoskeletal &Limb Development

Embryo Images Online External links below require Internet connection.

• Musculoskeletal Development
  • Musculoskeletal (Early Week 4)
  • Musculoskeletal (Late Week 4)

Developmental Biology (6th ed.) Gilbert:

NCBI Bookshelf external links below require Internet connection.

• Paraxial Mesoderm: The Somites and Their Derivatives
• Myogenesis: The Development of Muscle
• Osteogenesis: The Development of Bones

Video

Development Overview

Below is a very brief overview using simple figures of 3 aspects of early musculoskeletal development covering : Mesoderm then Somite and Limb development

More detailed overviews are shown on other notes pages (Mesoderm and Somite, Vertebral Column, Limb) in combination with serial sections and Carnegie images.

Mesoderm Development

Cells migrate through the primitive streak to form mesodermal layer. Extraembryonic mesoderm lies adjacent to the trilaminar embryo totally enclosing the amnion, yolk sac and forming the connecting stalk.

Paraxial mesoderm accumulates under the neural plate with thinner mesoderm laterally. This forms 2 thickened streaks running the length of the embryonic disc along the rostrocaudal axis. In humans, during the 3rd week, this mesoderm begins to segment. The neural plate folds to form a neural groove and folds.

Segmentation of the paraxial mesoderm into somites continues caudally at 1 somite/90minutes and a cavity (intraembryonic coelom) forms in the lateral plate mesoderm separating somatic and splanchnic mesoderm.

Note intraembryonic coelomic cavity communicates with extraembryonic coelom through portals (holes) initially on lateral margin of embryonic disc.

Somites continue to form. The neural groove fuses dorsally to form a tube at the level of the 4th somite and "zips up cranially and caudally and the neural crest migrates into the mesoderm.

Next Somite Development

Somite Development

Mesoderm beside the notochord (axial mesoderm) thickens, forming the paraxial mesoderm as a pair of strips along the rostro-caudal axis.

Paraxial mesoderm towards the rostral end, begins to segment forming the first somite. Somites are then sequentially added caudally. The somitocoel, is a cavity forming in early somites, which is lost as the somite matures.

Cells in the somite differentiate medially to form the sclerotome (forms vertebral column) and laterally to form the dermomyotome.

The dermomyotome then forms the dermotome (forms dermis) and myotome (forms muscle).

Neural crest cells migrate beside and through somite.

The myotome differentiates to form 2 components dorsally the epimere and ventrally the hypomere, which in turn form epaxial and hypaxial muscles respectively. The bulk of the trunk and limb muscle coming from the Hypaxial mesoderm. Different structures will be contributed depending upon the somite level.

References

Reviews | Articles | Search NCBI Bookshelf | Search PubMed

Reviews

Kaplan KM, Spivak JM, Bendo JA. Embryology of the spine and associated congenital abnormalities. Spine J. 2005 Sep-Oct;5(5):564-76.

Monsoro-Burq AH. Sclerotome development and morphogenesis: when experimental embryology meets genetics. Int J Dev Biol. 2005;49(2-3):301-8.

Christ B, Huang R, Wilting J. The development of the avian vertebral column. Anat Embryol (Berl). 2000 Sep;202(3):179-94.

Articles

Erwin WM, Inman RD. Notochord cells regulate intervertebral disc chondrocyte proteoglycan production and cell proliferation. Spine. 2006 May 1;31(10):1094-9.

Bird NC, Mabee PM. Developmental morphology of the axial skeleton of the zebrafish, Danio rerio (Ostariophysi: Cyprinidae). Dev Dyn. 2003 Nov;228(3):337-57.

Search NCBI Bookshelf: Bookshelf - vertebra development

Molecular Cell Biology - Effect of loss-of-function mutations in Hox-4 paralogs on development of cervical vertebrae in mice

Search PubMed: Search May 2006 "vertebra development" 4,001 reference articles of which 386 were reviews.

Search term = vertebra development

Glossary of Terms

A |B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W |X | Y | Z

Terms

• annulus fibrosus the circularly arranged fibers (derived from sclerotome)that together with the nucleus pulposus (derived from notochord) form the intervertebral disc (IVD) of the vertebral column.
• axial mesoderm (=notochord)
• cartilage connective tissue from mesoderm in the embryo forms initial skeleton replaced by bone. In adult, found on surface of bone joints.
• centrum the primordium of the vertebral body formed initially by the sclerotome.
• clavicle (L. little key) bone which locks shoulder to body.
• connective tissue-
• costotransverse
• costovertebral
• dermatome
• dermomyotome- dorsolateral half of each somite that forms the dermis and muscle.
• ectoderm the layer (of the 3 germ cell layers) which form the nervous system from the neural tube and neural crest and also generates the epithelia covering the embryo.
• endochondrial ossification the process of replacement of the cartilagenous framework by osteoblasts with bone.
• epaxial myotome the dorsal portion of the myotome that generates dorsal skeletal muscles (epaxial muscles).
• erector spinae
• extracellular matrix material secreted by and surrounding cells. Consists if fibers and ground substance.
• fibroblast growth factors (FGF) a family of at least 10 secreted proteins that bind membrane tyrosine kinase receptors. A patterning switch with many different roles in different tissues. (FGF8 = androgen-induced growth factor (AIGF)
• fibroblast growth factor receptor- receptors comprise a family of at least 4 related but individually distinct tyrosine kinase receptors (FGFR1- 4). They have a similar protein structure, with 3 immunoglobulin-like domains in the extracellular region, a single membrane spanning segment, and a cytoplasmic tyrosine kinase domain.
• growth factor usually a protein or peptide that will bind a cell membrane receptor and then activates an intracellular signaling pathway. The function of the pathway will be to alter the cell directly or indirectly by changing gene expression. (eg shh)
• hox (=homeobox) family of transcription factors that bind DNA and activate gene expression. Expression of different Hox genes along neural tube defines rostral-caudal axis and segmental levels.
• hypaxial myotome the ventral portion of the myotome that generates ventral skeletal muscles (hypaxial muscles).
• intercostal the region between adjacent ribs, usually comprising intercostal muscles and connective tissue.
• intervertebral disc (IVD) the annulus fibrosus+nucleus pulposus together form the intervertebral disc (IVD) of the vertebral column. This is the flexible region between each bony vertebra that allows the column to be bent.
• intervertebral foramina-
• lumbar plexus mixed spinal nerves innervating the lower limb form a complex meshwork (crossing).
• mesoderm the middle layer of the 3 germ cell layers of the embryo. Mesoderm outside the embryo and covering the amnion, yolk and chorion sacs is extraembryonic mesoderm.
• myoblast the undifferentiated mononucleated muscle cells that will fuse together to form a multinucleated myotube, then mature into a muscle fibre.
• MyoD transcription factor involved in the determination of muscle cells in the somite. A basic helix-loop-helix factor which binds DNA.
• myotome the portion of the dermamyotome that generates skeletal muscle. Has 2 components epaxial (dorsal muscles ) hypaxial (ventral muscles).
• neural crest cell region at edge of neural plate, then atop the neural folds, that remains outside and initially dorsal to the neural tube when it forms. These paired dorsal lateral streaks of cells migrate throughout the embryo and can differentiate into many different cell types(=pluripotential). Those that remain on the dorsal neural tube form the sensory spinal ganglia (DRG). Neural crest cells migrate into the somites.
• neural tube neural plate region of ectoderm pinched off to form hollow ectodermal tube above notochord in mesoderm.
• neuropore opening at either end of neural tube: cranial=rostral=anterior, caudal=posterior. The cranial neuropore closes (day 25) approx. 2 days (human) before caudal.
• nucleus pulposus central region of intervertebral discs of the spinal cord derived from the notochord.
• notochord rod of cells lying in mesoderm layer ventral to the neural tube, induces neural tube and secretes sonic hedgehog which "ventralizes" the neural tube and may influence somite development.
• Pax name derived from Drosophila gene 'paired' (prd) the 'paired box' is a amino end 124 amino-acid conserved domain (signature aa 35-51: P-C-x(11)-C-V-S). Transcription factor of the helix-turn-helix structural family, DNA binding, and activating gene expression. In human, nine member proteins from Pax-1 to Pax-9. Regulate differentiation of many different tissues. Some members of the family (PAX3, PAX4, PAX6, PAX7) also contain a functional homeobox domain.
• pedicle
• sacrum
• sclerotome ventromedial half of each somite that forms the vertebral body and intervertebral disc.
• segmentation to break a solid structure into a number of usually equal size pieces.
• spinal cord caudal end of neural tube that does not contribute to brain. Note: the process of secondary neuralation contributes the caudal end of the spinal cord.
• spinal ganglia (=dorsal root ganglia, drg) sensory ganglia derived from the neural crest lying laterally paired and dorsally to the spinal cord (in the embryo found ventral to the spinal cord). Connects centrally with the dorsal horn of the spinal cord.
• spinal nerve mixed nerve (motor and sensory) arising as lateral pairs at each vertebral segmental level.
• somatic mesoderm derived from lateral mesoderm closest to the ectoderm and separated from other component of lateral mesoderm (splanchnic, near endoderm) by the intraembryonic coelom.
• somite segmental block (ball) of mesoderm formed from paraxial mesoderm adjacent to notochord (axial mesoderm). Differentiates to form initially sclerotome and dermamyotome (then dermotome and myotome).
• somitic mesoderm
• somitocoel a transient cavity that appears within each of the the early forming somites then is lost.
• somitogenesis the process of segmentation of the paraxial mesoderm to form "mesoderm balls" beginning cranially (humans day20) and extending caudally at 1 somite/90 minutes until approx. 44 pairs have been formed.
• sonic hedgehog (=shh) secreted growth factor that binds patched (ptc) receptor on cell membrane. SHH function is different for different tissues in the embryo. In the nervous system, it is secreted by the notochord, ventralizes the neural tube, inducing the floor plate and motor neurons. In the Limb it is secreted by the zone of polarizing activity (ZPA) organizing limb axis formation.
• tarsal
• Tbx T-box genes (transcription factor) involved in mouse forelimb (Tbx4) and hindlimb (Tbx5) specification.
• transcription factor a factor (protein or protein with steroid) that binds to DNA to alter gene expression, usually to activate. (eg steroid hormone+receptor, Retinoic acid+Receptor, Hox, Pax, Lim, Nkx-2.2).
• transverse abdominal m.
• trochanter
• vertebral body formed by centrum, vertebral arch, facets for ribs. It is the mature vertebral structure formed by the 5 secondary ossification centers after puberty.
• vertebral column name given to the complete structure formed from the alternating segments of vertebra and intervertebral discs which support the spinal cord.
• vertebral foramen the dorsal cavity within each vertebra, generated by the vertebral arch that surrounds the spinal cord.
• vertebral canal
• Wnt7a The designation 'Wnt' was derived from 'wingless' and 'int'. The Wnt gene was first defined as a protooncogene, int1. Humans have at least 4 Wnt genes: Wnt7a gene is at 3p25 encoding a 349aa secreted glycoprotein. A patterning switch with different roles in different tissues. The mechanism of Wnt distribution (free diffusion, restricted diffusion and active transport) and all its possible cell receptors are still being determined. At least one WNT receptor is Frizzled (FZD). The Frizzled gene family encodes a seven-transmembrane receptor.

Quick Links

Development Notes ----------------- Menstrual Cycle Week 1 Week 2 Week 3 Week 4 Placenta Serial Images Genes/DNA Molecular Dev Abnormal Dev Postnatal Dev Notes Index

System Notes ----------------- Heart/Cardiovascular Respiratory Coelomic cavity Gastrointestinal Tract Head and Neck Neural Neural Crest Eye Ear Nose Endocrine Urogenital Musculoskeletal Integumentary

Movies ----------------- Embryo Growth Ultrasound Week 1 Week 2 Week 3 Week 4 Stage 13/14 Stage 22 Neural Head and Neck Heart Vasculature Gastrointestinal Urogenital Other Embryos Larsen Internet

Other Embryos ----------------- Chicken Fly Frog Mouse Rabbit Rat Worm Zebrafish Guinea Pig

UNSW Embryology ISBN: 978 0 7334 2609 4

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