Week 9/10: Morphogens and Other Signalling Receptors

• morphogenesis is the biological process of pattern formation that allows the organization of differentiated cells into specific and specialized structures like tissues/organs

  • stimulated by a combination of chemical and mechanical factors
  • controls the organized spatial distribution of cells during embryonic development
  • can occur in mature organisms for tissue homeostasis (major source of morphogenesis) or stem cell regeneration after tissue damage

  
• morphogens are paracrine analog signalling molecules (chemical/peptide/protein) that define cell fate in a concentration dependent manner, forming gradients across tissues or compartments, cause developmental changes in tissues/organisms

  • affect cellular process that stimulate cell movement or alter transcriptional profile of a cell
  • influence cell/cell adhesion (relocation)
  • changing composition of ECM
  • alter shape/size of cell

  
• function 1: morphogens influence cell/cell adhesion

  • cells can bind to one another using membrane anchored extracellular proteins called cell adhesion molecules (CAM) which have self complementary sequences that allow binding
  • morphogens influence expression of different CAM thus affecting how cells attach to each other

  
• function 2: morphogens influence composition of ECM (cancer cells hijack this function to be motile)

  • ECM -> dynamic network of macromolecules/minerals that provide structural/biochemical support to surrounding cells
  • consists of proteins, enzymes, polymers, glycoconjugates, proteoglycan, carbohydrates that coat each cell/monolayer of cells
  • ECM aids in cell separation and can create a system where cells can move from 1 location to another

  
• function 3: morphogens influence cell contraction (cell shape/size)

  • morphogens stimulate production of proteins involved in cell contraction like actin and myosin
  • this increased production of contractile proteins can change cell shape to make a mechanical force on adjacent cells -> transcriptional expression differences or cell differentiation
• morphogens are typically released from a specific cell type (they have limited synthesis and secretion)

  • achieved through paracrine/endocrine signalling
  • are analog signals since they can achieve multiple outcomes based on concentration present
  • cell secretes morphogen -> morphogen diffuses and establish gradient from origin site -> cells receiving morphogen respond differently to morphogen concentration
• tissue specific competence, morphogen dynamics, signalling dynamics, and transcriptional networks contribute to the french flag model which is

  • cells differentiating into distinct types based on morphogen concentration gradients

  
• morphogen gradients determine signalling outcomes

  • in HIGH concentration of morphogen, it binds to a receptor that causes signalling pathway to turn on -> can cause TF1 to turn on which binds to positively regulated low affinity binding site on gene A -> gene A products do its function AND bind to gene B to inhibit it while TF1 binds to negatively regulated high affinity TF binding site on gene C to keep off
• morphogen gradients determine signalling outcomes

  • in MODERATE concentrations, there's less TF1 activation thus less gene A product to inhibit gene B so that gets turned on while gene A activity is decreased, still enough TF1 to bind to high affinity gene C to keep ofF
• morphogen gradients determine signalling outcomes

  • in LOW concentrations, there is little to no TF1 to inhibit gene C (thus little to no gene A activation) so it's expressed while its products inhibit gene B expression
• neurulation occurs after germ layer formation which make up the whole organism

  • endoderm -> forms structures like endothelial layer of GI tract, kidneys, lungs, livers, pancreas, etc.
  • ectoderm -> forms skin and nervous system
  • mesoderm -> forms muscular, skeletal, cardiovascular, excretory, and reproductive systems

  
• the notochord (NC) is a cylindrical rod of cells that spans the entire length of the developing embryo and directs the thickening of the ectodermal cells to form the neural plate, forms around the mesoderm, this structure helps to secrete factors for neurulation for the spinal cord and other structures in embryogenesis

  
• in neural tube formation: the notochord simulates the outward motion of the MESODERM which causes inward folding/collapse of the ECTODERM neural plate -> invagination and linking of neural folds -> neural tube formed which forms central NS (brain/spinal cord) AND neural crest formed, forms peripheral NS (ganglia)

  
• morphogens direct unique patterns of gene expression in drosophila embryo like

  • FGF from posterior to anterior
  • retinoic acid from anterior to posterior
  • Shh from ventral to dorsal from the NC
  • ^these TF are activated by different concentrations and combinations of morphogens at each cell, forms a 3D gradient

  
• the primitive streak runs around the mesoderm area which is what gives rise to the notochord

  
• 3 key receptor signalling pathways important for development are

  • Wnt
  • Hedgehog
  • Notch
• Wnt, Notch, and Hedgehog are all morphogens involved in development

  • they act in very short range distances (paracrine, juxtacrine) and form gradients that specify different fates at different ligand concentrations
  • * cells distinctly respond to different concentrations of morphogen