L17 muscle and skeleton

Mesoderm Regions

• The mesoderm differentiates into three regions: paraxial, intermediate, and lateral plate mesoderm.

Paraxial Mesoderm & Somites

• Paraxial mesoderm becomes somites, which are the main source of skeletal muscle.
• Somitomeres are segments of the paraxial mesoderm that develop into somites through complex signaling processes.
• Somitogenesis refers to the process of forming somites.
• Somites are crucial for organizing the segmental pattern of vertebrate embryos.
• They determine the migration paths of neural crest cells, guiding them to their destinations.
• Somites form vertebrae and ribs, skin, skeletal muscle, and the body walls and limbs.
• The number of somites corresponds to specific body regions, with lower numbers indicating more cranial muscles and higher numbers associated with caudal parts.

Somite Formation Timeline

• After the 25th day, 3-4 somites are formed per day.
• Humans form 42-44 somite pairs.
• Several caudal somites disappear, resulting in 35-37 pairs.
• The number of somites is used to determine the embryo's age.

Intermediate and Lateral Plate Mesoderm

• Intermediate mesoderm becomes the urogenital tract.
• Lateral plate mesoderm splits into two layers, forming the body wall, digestive tract wall, and limbs.

Molecular Events in Somite Differentiation

• Ectoderm induces somite differentiation through Wnt6, which stimulates the expression of the transcription factor Paraxis.
• Paraxis, expressed in newly forming somites, leads to mesenchymal-epithelial transition.
• Notochord induces Pax1 and Pax9 expression ventrally in the somite via Shh and noggin, forming the sclerotome.
• Sclerotome cells proliferate, lose N-cadherin, and undergo epithelial-mesenchymal transition.
• Ectoderm and neural tube influence the dorsal half of the somite, forming the dermomyotome through Wnt genes.
• The dermomyotome expresses Pax3, Pax7, Paraxis, and Noggin.
• Mesenchymal cells from the dermomyotome form the myotome beneath the remaining somatic epithelium, now called the dermatome.

Skeletal System Overview

• The skeletal system includes bones, cartilage, ligaments, and connective tissues, providing structural support, mineral and lipid storage, blood cell production, protection, and leverage.

Origins of Skeletal Tissues

• Skeletal tissues originate from cells of varying mesenchymal origins
• The axial skeleton originates from the sclerotome
• The appendicular skeleton originates from mesenchyme of the lateral plate mesoderm (somatic mesoderm)
• The head skeleton originates from paraxial mesoderm and neural crest cells

Modes of Osteogenesis

• Osteogenesis involves transforming mesenchymal tissue into bone tissue through endochondral and intramembranous ossification.

Endochondral Ossification

• Mesenchymal cells differentiate into a cartilage model, which is then replaced by bone.
• Forms long bones like those in the arms and legs.

Intramembranous Ossification

• Direct ossification of mesenchyme occurs without a cartilage intermediate
• Forms flat bones, such as superficial bones of the face and skull.

Endochondral Ossification Steps

• Chondrocytes enlarge and die, and the matrix gets calcified at the center of growing cartilage.
• Osteoblasts cover the cartilage shaft with a thin layer of bone.
• Blood vessels penetrate the cartilage, and new osteoblasts form a primary ossification center.
• The bone of the shaft thickens, and cartilage near each epiphysis is replaced by bone shafts.
• Blood vessels invade the epiphysis, and osteoblasts form secondary ossification centers.
• Osteocytes are mature bone cells, while osteoblasts create bone and are maintained in the marrow cavity.

Intramembranous Ossification Steps

• An ossification center appears in the fibrous connective tissue membrane as mesenchymal cells cluster and differentiate into osteoblasts.
• Osteoblasts secrete bone matrix (osteoid), which mineralizes, trapping osteoblasts that become osteocytes.
• Woven bone and periosteum form as osteoid is laid down between embryonic blood vessels, creating trabeculae.
• A bone collar of compact bone forms, and red marrow appears as trabeculae thicken; spongy bone persists internally, and its vascular tissue becomes red marrow.

Molecular Events in Bone Formation

• Two developmental programs, osteogenic and chondrogenic, depend on the intermediate environment.
• Each program involves different transcription factors and cell adhesion molecules
• N-cadherin promotes transformation of preskeletal mesenchymal cells to an epithelial-like morphology
• TGF-β stimulates synthesis of fibronectin and N-CAM, maintaining cells in a preskeletal state and allowing differentiation.

Major Steps in Bone Differentiation

• Osteogenic program (intramembranous ossification):
  • Runx2 transcription factor controls differentiation of mesenchymal cells into osteoblasts and causes expression of bone proteins
  • Osterix (Osx) is also required for osteoblast differentiation
• Chondrogenic program (endochondral ossification):
  • Sox-9 allows chondroblasts begin forming collagen and matrix; some remains cartilage and continue to express Sox-9
  • Cartilage to bone influenced by Ihh (Indian hedgehog) and BMP-6, which induce osteoblast formation from chondroblasts

Muscle Types

• Three muscle types form during embryonic development: skeletal, cardiac, and smooth muscle.
• Skeletal muscle is striated and under voluntary control
• Cardiac muscle is striated and under involuntary control
• Smooth muscle is not striated and under involuntary control

Muscle Origins

• Skeletal muscle derives from paraxial mesoderm (somites or somitomeres)
• Cardiac and smooth muscles of the gut and respiratory tract derive from splanchnic mesoderm
• Smooth muscles of blood vessels and arrector pili muscles derive from local mesenchyme.

Skeletal Muscle Functions

• Skeletal muscles produce skeletal movement, maintain posture, support soft tissues, guard entrances/exits, and maintain body temperature.

Skeletal Muscle Development

• All skeletal muscles originate from somites
• Myogenic cells originate from the myotome of the somite and are precursors to most muscle cells
• These cells undergo mitotic divisions and become post-mitotic myoblasts.
• FGF and TGF-β keep myogenic cells proliferating
• Upregulation of p21 removes them from the cell cycle, forming post-mitotic myoblasts.
• Growth factors stimulate myoblasts to transcribe mRNA for actin and myosin.
• Myoblasts fuse, forming myotubes and synthesizing proteins.
• Myofibrils are formed from various proteins, and contractile elements arrange into sarcomeres.

Cardiac Muscle Development

• Early cardiac myoblasts contain myofibrils and undergo contractions
• Cardiac myocytes partially disassemble filaments during mitosis and do not fuse but remain individual cells
• Intercalated disks join adjacent cells.

Skeletal Anomalies: Osteogenesis Imperfecta

• Osteogenesis imperfecta affects 1/15,000 births
• Caused by a defect in the gene producing type 1 collagen
• Results in bowed legs, scoliosis, and multiple bone fractures.

Muscular Anomalies: Prune Belly Syndrome

• Prune belly syndrome affects 1/40,000 births
• Cause is largely unknown but there is a possible genetic defect
• Characterized by poor development of abdominal muscles, undescended testes, and urinary tract problems
• Many infants are stillborn or die with severe lung or kidney complications.

Myostatin

• Myostatin stops the production of muscle
• A lack of myostatin leads to over production of muscle