Somitogenesis is a crucial process in early development, forming segmented blocks of mesoderm along the embryo's axis. These somites later differentiate into vertebrae, ribs, and muscles. It's a perfect example of how complex structures arise from simpler precursors.

The molecular clock and wavefront model explains how somites form at regular intervals. Oscillating gene expression acts as a clock, while signaling gradients create a moving wavefront. This interplay ensures precise timing and positioning of somite boundaries as the embryo grows.

Somitogenesis and Somite Formation

Paraxial Mesoderm and Somite Development

• Somitogenesis forms paired blocks of mesoderm (somites) along the anterior-posterior axis of the embryo
• Paraxial mesoderm located on either side of the neural tube and notochord generates somites
• Somites bud off from the presomitic mesoderm (PSM) in a rostral-to-caudal direction at regular intervals
• PSM divides into more mature anterior region and less differentiated posterior region
• Somite formation involves epithelialization of mesenchymal cells in anterior PSM creating spherical structure
  • Outer epithelial layer surrounds mesenchymal core
• Species-specific somite formation varies in number and timing
  • Humans form 42-44 somite pairs over ~4 weeks

Somite Formation Process

• Mesenchymal cells in anterior PSM undergo epithelialization
• Cells reorganize and polarize to form epithelial outer layer
• Extracellular matrix deposition occurs between forming somites
• Somite boundaries established through differential cell adhesion
• Newly formed somites separate from PSM through a "budding off" process
• Each somite develops distinct anterior and posterior compartments
• Somite maturation continues as new somites form caudally

Molecular Clock and Wavefront Model

Clock Component

• Oscillating gene expression in PSM creates temporal periodicity for somite formation
• Key oscillating genes belong to Notch, Wnt, and FGF signaling pathways
• Gene expression cycles match somite formation periodicity
• Hes genes act as transcriptional repressors regulating clock gene oscillations
• Cyclic gene expression propagates as waves through the PSM
• Oscillations synchronized between neighboring cells through cell-cell communication

Wavefront Component

• Moving front of gene expression progresses caudally defining somite competence region
• Opposing gradients establish wavefront:
  • FGF/Wnt (high posterior to low anterior)
  • Retinoic acid (high anterior to low posterior)
• Gradients create "determination front" where cells become competent to form somites
• FGF and Wnt maintain PSM in undifferentiated state
• Retinoic acid promotes somite differentiation
• Intersection of clock oscillations and wavefront determines somite boundary formation
• Model explains regular interval formation and consistent somite size despite embryonic growth

Notch and Wnt Signaling in Segmentation

Notch Pathway in Molecular Clock

• Notch signaling establishes molecular clock oscillations within PSM
• Cyclic expression of Notch pathway components (receptor, ligands like Delta)
• Notch activation induces Hes gene expression
• Hes proteins repress own transcription creating negative feedback loop
• Oscillations propagate through PSM via synchronized Notch signaling
• Disruption of Notch signaling leads to somite formation defects (irregular boundaries)

Wnt Signaling in Clock and Wavefront

• Wnt pathway contributes to both molecular clock and wavefront components
• Maintains undifferentiated state of PSM cells
• Regulates expression of key segmentation genes (T-box transcription factors)
• Wnt signaling gradually declines from posterior to anterior PSM
  • Helps establish determination front for somite competence
• Cyclic Wnt target genes (Axin2) contribute to molecular clock mechanism
• Wnt signaling interacts with FGF pathway to regulate PSM maturation

Pathway Interactions

• Cross-talk between Notch, Wnt, and FGF pathways coordinates somite formation
• Notch and Wnt oscillations coupled through shared target genes
• FGF signaling modulates Notch and Wnt activity in PSM
• Retinoic acid antagonizes FGF/Wnt signaling to promote somite differentiation
• Integration of multiple signaling inputs ensures robust segmentation process
• Mutations in pathway components lead to vertebral abnormalities (scoliosis)

Somite Differentiation into Sclerotome, Myotome, and Dermatome

Sclerotome Formation

• Sclerotome forms from ventromedial portion of somite
• Gives rise to vertebrae and ribs
• Induced by signals from notochord and floor plate
  • Primary signal: Sonic hedgehog (Shh)
• Shh activates Pax1 expression in sclerotome
• Sclerotome cells undergo epithelial-to-mesenchymal transition
• Migrates around notochord and neural tube to form vertebral bodies
• Sclerotome patterning establishes vertebrae segmentation (resegmentation)

Myotome Development

• Myotome develops from dorsolateral portion of somite
• Gives rise to skeletal muscles of trunk and limbs
• Influenced by signals from dorsal neural tube and surface ectoderm
  • Key signals: Wnt proteins and bone morphogenetic proteins (BMPs)
• Myogenic regulatory factors (MRFs) drive muscle cell differentiation
  • MyoD, Myf5, myogenin, MRF4
• Myotome cells form early muscle fibers and muscle progenitor cells
• Progenitors migrate to form limb and body wall muscles

Dermatome Specification

• Dermatome forms from dorsal-most region of somite
• Gives rise to dermis of the back
• Regulated by BMP signaling from dorsal neural tube and surface ectoderm
• Dermatome maintains epithelial characteristics longer than other somite regions
• Cells eventually undergo EMT and migrate to form dermis
• Dermatome patterning influenced by positional cues along the body axis
• Contributes to regional specialization of skin (scales, feathers, hair follicles)