Chapter 12: Paraxial and Intermediate

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  1. Mesoderm
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    Mesoderm generates all organs between ectodermal wall and endodermal tissue

    Mesoderm is divided into 5 regions

    1.Chordamesoderm --> Notochord

    2.Paraxial mesoderm (somitic dorsal mesoderm): --> Somites --> produces connective tissues (bone, muscle, cartilage, dermis)

    3.Intermediate mesoderm: -->Urino-genital system

    4.Lateral plate mesoderm: -->  heart, blood vessels and blood cells, lining of body cavities, extra-embryonic membranes (fetal nutrition)

    5.Head mesenchyme: musculature of face
  2. Specification of Mesoderm
    Mesoderm is specified in mediolateral axis

    Different concentrations of BMP induce differential expression of Fox family transcription factors

    Foxf1 (forkhead family of  transcription factors) is expressed in lateral plate mesoderm 

    - Foxc1 and Foxc2 - paraxial mesoderm --> somites 

    - Depletion of Foxc1 and Foxc2 --> expression of Pax2 --> intermediate mesoderm
  3. Somites
    - give segmental pattern to vertebrate embryo 

    - determine the path of neural crest cells and spinal nerve axons 

    - give rise to cells that form vertebrae, ribs, dermis and skeletal muscles
  4. Somite Formation
    Number of somites is characteristic of each species: chick – 50, mice – 65 and snakes - 500

    • Somite formation includes: 
    • – periodicity 
    • - epithelialization 
    • - specification 
    • - differentiation

    • Paraxial cells condense into Somitomeres   
    •     --> compact and bound together by epithelium  
    •     -->separate into somites
  5. Somite formation and Hairy gene
    Image Upload 2•Expression of hairy1 gene in caudal half of each somite as well as posterior portion of presomitic mesoderm

    •Caudal fissure (small arrow in B) begins to separate somite from presomitic mesoderm

    •Posterior region of hairy gene expression extends anterior and progressively the band shortens

    •Another band of hairy 1 expression starts --> moves anteriorly like a wave

    •Band of hairy1 gene expression in pre-somitic mesoderm is the site of pinching-off of a new somite
  6. Separation of Somites
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    • Hairy1 gene --> targets ephrin genes (Ephrin B2) and its receptor (EphA4 – tyrosine kinase)

    Formation of Somite boundary between EphrinB2 in the posterior of the somite and EphA4 on the anterior portion of presomite mesoderm

    Budding off of somites coincide with the expression of EphA4

    Somitogenesis progresses caudally

    Epithelialization - N-cadherin helps in conversion of loose mesenchymal cells to epithelial somite
  7. Somite Specification and Commitment
    Axis specification:  

    • Somites form different structures at different positions along A-P axis 
    •     - Ribs in thoracic region 
    •     - Vertebrae in other regions 

    Somites that form cervical vertebrae cannot form ribs    

    Axis specification is mediated by Hox genes
  8. Lunatic Fringe Protein
    Somitogenesis – occurs simultaneously with the regression of primitive streak

    Cells passing through Hansen’s node secrete FGF8 --> prevents Lunatic fringe protein

    Regression of Hansen’s node --> FGF8 producing cells move posteriorly --> activation of Lunatic fringe protein --> somitogenesis
  9. Periodicity– Notch pathway
    Periodicity - first somite appears in the anterior portion - new somites bud off at regular intervals

    Notch signaling pathway – cells from presumptive somite boundary are transplanted into a region of unsegmented mesoderm   

    •     --> activation of Lunatic fringe protein  
    •     --> activation of notch pathway --> new somite boundary

    Addition of Lunatic fringe protein to non-boundary cells --> formation of boundary --> somites
  10. Spondylocostal dysplasia - Delta-like3 (DLL3) gene
    Mutations in Notch signaling --> aberrant vertebrae

    DLL3 – delta-like3 gene encodes a ligand for Notch

    Mutations of DLL3 in humans --> spondylocostal dysplasia (defects in vertebrae and ribs)
  11. Differentiation within the Somite
    - give rise to cells that form vertebrae, ribs, dermis, skeletal muscles

    Sclelorotome – precursor of bone

    Myotome – precursor of muscle
  12. Dermamyotome
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    • – cells from two lateral regions --> divide --> produce a lower layer of myoblasts (muscle precursor cells)  

    Epaxial (Primaxial) --> deep muscles of back 

    Hypaxial (Abaxial) --> body wall, limbs and tongue

    Central region of dermamyotome --> dermis of back skin
  13. Factors involved in Patterning of Somites
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    •BMP4 from dorsal epidermis induces Wnt. family of proteins in Somites

    •Wnt + low conc. of Shh -->induce Primaxial myotome --> myogenic transcription factor Myf5

    Neurotropin (NT3) from neural tube --> Dermatome

    Wnt from ectoderm + BMP4 from lateral plate mesoderm --> Abaxial myotome

    Wnt + high conc. of Shh --> Pax1 expression --> Sclerotome
  14. Myogenesis
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    Somites --> Primaxial and Abaxial myotome --> myoblasts (muscle cell precursors) --> respond to FGF --> multiply

    Pax3 --> Myf5 and MyoD (muscle specific transcription factors) --> induce muscle specific genes (Creatine phosphokinase, Acetylcholine receptor and its own gene (MyoD)

    Myotubes: Myoblasts stop division --> secrete fibronectin --> bind with integrin (in ECM) --> fuse together to form multinucleated myotubes (committed to become muscle fibers)

    Alignment: myoblasts come together into chains (mediated by glycoproteins and cadherins)

    • Fusion of cell membrane is activated by movement of Ca++, mediated by metalloproteases (meltrins)
    • Maturation of muscle fiber - ready for muscular  contraction
  16. Osteogenesis
    Lineages to generate skeleton:  Somites --> axial skeleton. Lateral plate mesoderm --> limb skeleton. Cranial neural crest --> branchial arch and craniofacial bones.

    • Modes of Osteogenesis
    • Intramembrane ossification – direct conversion of mesenchymal cells into bone 

    Endochondral ossification – mesenchymal cells differentiate into cartilage --> later replaced by bone
  17. Intramembrane Ossification
    Osteogenic precursor cells proliferate --> condense into compact nodules --> some develop into capillaries and others into osteoblasts (bone precursor cells)

    Osteoblasts deposit osteoid matrix --> osteoblasts arrayed along calcified region of matrix --> become trapped --> osteocytes (bone cells)
  18. CBFA1 gene – Cleidocranial Dysplasia
    Intramembrane ossification is mediated by BMPs and CBFA1 proteins.

    Mutations in CBFA1 – cleidocranial dysplasia (defects in skull and shoulders due to poor osteoblast differentiation)
  19. Endochondral Ossification
    1. Mesenchymal cells committed to become cartilagenous cells (facilitated by Pax1 and Scleraxis)

    2. Mesenchymal cells condense --> Compact nodule --> differentiate into chondrocytes (cartilagenous cells) (initiated by N-cadherin; SOX9 gene)

    3. Chondrocytes in the  center divide rapidly

    4. Chondrocytes stop dividing and undergo hypertrophy and apoptosis --> mineralize their extra cellular matrix --> form bone marrow

    5. Invasion of blood vessels

    As cartilage cells die à cells surrounding cartilage model differentiate into osteoblasts -->  form bone matrix Slowly cartilage is replaced with bone

    Osteoclasts: derived from same precursors of macrophages -->  enter bone  marrow through  blood vessels -->  pump H+ ions -->  acidify and hollow  out bone marrow  for erythropoiesis
  20. Osteoporosis and Ostepetrosis
    Osteroporosis: Number of osteoclasts is tightly regulated - too much activity of osteoclasts --> too much bone is dissolved  A condition accelerated in women during   menopause (hormones)

    Osteropetrosis: rare congenital disorder in which the bones become overly dense. This results from an imbalance between the formation of bone (osteoblasts) and the breakdown of the bone by osteoclasts
  21. Intermediate Mesoderm – Kidney formation
    Intermediate mesoderm --> Urinogenital system (kidneys, gonads and respective duct systems)

    Kidney: functional unit is nephron (12 cell types, 10,000 cells) – Glomerulus –coiled blood capillary  Bowman’s capsule – cup-shaped structure around glomerulus

    Kidney function: 180 L blood  filtered @ 1.2 L /min  99% reabsorbed in  tubules (salts, water,  metabolites)  remaining concentrated     fluid is excreted
  22. Development of Kidney
    Stage 1: On day 22 (human) – Pronephric duct arises in intermediate mesoderm (just ventral to anterior somites)  - cells migrate caudally

    Stage 2: As pronephric tubules degenerate, middle portion of nephric duct induces kidney tubes (Mesonephros) differentiate

    In Females - undergoes apoptosis - source of hematopoietic stem cells.

    In Males - vas deferens

    Stage 3: Metanephros (functional kidney in reptiles, birds and mammals) – generated by interactions of epithelial and mesenchymal cells of intermediate mesoderm
  23. Reciprocal Induction
    Metanephric mesenchyme --> induces formation of a branch from each nephric duct, ureteric buds

    • Ureterine buds enter metanephric mesenchyme --> mesenchyme induces buds
    • to branch

    -At tips, the bud epithelium induces mesenchyme to condense -->differentiate into nephrons.

    - Which induces ureterine bud to branch and grow
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Chapter 12: Paraxial and Intermediate
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