Mesoderm

The mesoderm is the middle of the three primary germ layers formed during gastrulation in early embryonic development. Situated between the ectoderm externally and the endoderm internally, it plays a fundamental role in establishing the structural and functional framework of most animal bodies. In vertebrates, mesodermal tissues contribute to the musculoskeletal, circulatory, urogenital, and connective tissue systems. Its development is orchestrated through intricate signalling pathways that govern cell migration, differentiation, and body patterning.

Formation and Differentiation

The mesoderm arises during the third week of embryogenesis through gastrulation, a process initiated by the formation of the primitive streak on the epiblast surface. Epiblast cells migrate toward the streak and invaginate. Some form the endoderm by displacing hypoblast cells, while others settle between the ectoderm and endoderm to create the mesoderm. Cells remaining at the surface become the ectoderm.
Differentiation is mediated by intercellular signals, notably fibroblast growth factors that establish cell polarity and drive mesoderm formation. β-catenin stabilisation in specific regions determines organiser position, influencing transcriptional activation through interactions with TCF proteins. These events initiate gene expression essential for mesodermal identity. The mesoderm also exerts inductive effects on surrounding tissues, for example stimulating the overlying ectoderm to form the neural plate.

Regional Subdivisions

Four major subdivisions form within the mesoderm, each giving rise to distinct structures:
Axial mesodermThis central region forms the notochord, a rod-like structure essential for defining the body axis. The notochord induces neural tube formation and establishes cranial–caudal patterning.
Paraxial mesodermLocated adjacent to the notochord, the paraxial mesoderm segments into somitomeres and later somites. These paired blocks of tissue differentiate into:

• Sclerotome – forming cartilage, bone, and tendons of the axial skeleton
• Myotome – forming skeletal muscle
• Dermatome – forming the dermis of the back

Somite development is tightly regulated by signals from the neural tube, notochord, epidermis, and lateral plate mesoderm. Key molecular regulators include Sonic Hedgehog (inducing sclerotome formation), WNT proteins (regulating myotome and dermatome), and retinoic acid (maintaining bilateral segmentation synchrony).
Intermediate mesodermSituated between paraxial and lateral plate mesoderm, this region forms the urogenital system, including kidneys, gonads, associated ducts, and the adrenal cortex. Upper regions form nephrotomes, while caudal regions form the nephrogenic cord.
Lateral plate mesodermThis area splits into two layers:

• Somatic (parietal) layer – forms body wall structures with the overlying ectoderm
• Splanchnic (visceral) layer – forms the wall of the gut tube with the endoderm

The space between them becomes the intraembryonic coelom. From these layers arise the heart, blood vessels, blood cells, limb mesoderm, and serous membranes (peritoneal, pleural, and pericardial linings).

Developmental Timeline

Key mesodermal events occur during the third week:

• Days 13–15 – proliferation of extraembryonic and embryonic mesoderm; primitive streak expansion
• Days 15–17 – formation of the notochordal process
• Days 17–19 – establishment of the notochordal and axial canals; formation of the first somites

Somitogenesis proceeds in a cranial-to-caudal progression, producing well-defined segments that later contribute to the axial skeleton. By the fifth week, typical segmentation includes four occipital, eight cervical, twelve thoracic, five lumbar, five sacral, and eight to ten coccygeal somites.

Molecular Regulation of Mesoderm Patterning

Mesodermal patterning is governed by a network of signalling pathways:

• Sonic Hedgehog (SHH) from the notochord promotes sclerotome formation.
• WNT signals from the neural tube specify myotome and dermatome.
• Neurotrophin-3 assists in dermal patterning.
• PAX1 and PAX2 genes support cartilage, bone, and muscle development.
• FGF8 and WNT3a, balanced by retinoic acid, maintain segmentation rhythms and bilateral symmetry.

Segmentation clock desynchronisation can produce asymmetric somite formation, reflecting the sensitivity of the system to molecular disturbances.

Derivatives of the Mesoderm

The mesoderm gives rise to a wide range of tissues and organ systems, including:

• Skeletal, cardiac, and smooth muscle
• Connective tissues and dermis
• Vertebrae, ribs, and axial skeleton
• Blood vessels, heart, and circulatory system components
• Kidneys, gonads, and adrenal cortex
• Microglia, mesothelium, and dentin of teeth

Its contributions extend throughout the body, forming much of the structural and functional framework of vertebrate organ systems.

Stem Cell Potential and Clinical Relevance

Mesodermal derivatives can be generated experimentally from human embryonic stem cells. These cells exhibit multipotency, self-renewal, and the ability to form mesoderm-like tissues, including contractile muscle fibres and collagen-remodelling cell populations. Their potential supports research into regenerative therapies for musculoskeletal and cardiovascular disorders.
The study of mesodermal development continues to illuminate key mechanisms of embryogenesis, body patterning, and congenital anomaly formation. Signals governing mesoderm formation and somite differentiation are central to understanding vertebrate development and hold promise for future biomedical applications.