week 3

• Why are we interested signalling?

  A lot of birth defects that occur result from or result in signalling defects
• Signalling pathway components and principles

  Extracellular signalling molecules

  Receptors

  Intracellular signalling pathways

  Effector proteins
• Cell response to signalling

  Can be fast or slow

  
  

  Different response to the same signal
• Signaling molecules include...


  Proteins

  Small peptides

  Amino acids

  Nucleotides

  Steroids

  Retinoids

  etc.

  
  

  
  

  They typically act in very low concentrations
• Principles of cell communication

  Mediated mainly be extracellular signalling proteins

  
  

  Reception of signal usually requires receptor

  
  

  Binding activates receptors, activating intracellular signalling pathways

  
  

  Targets are generally effector proteins
• Effector proteins


  Cell communication generally effect these

  
  

  They implement change in cell behaviour

  
  

  Can be gene regulatory proteins, ion channels, metabolic pathway components
• Mechanisms required for cell communication


  To control which signals are emitted and when

  
  

  To enable the signal-receiving cell to interpret the signals
• Fast responses


  Changes in cell movement, secretion, metabolism

  
  

  Need not involve changes in gene transcription

  
  

  May involve rapid phosphorylation of effector proteins
• Slow responses


  Increases in cell growth and division

  
  

  Changes in gene expression
• Endocrine signalling


  Long distance signalling involving hormones travelling through blood stream
• Synaptic signalling


  a nerve cell releases nerotransmitter molecules into the synapse, stimulating the target cell
• Issues of synaptic signalling

  Critical for signalling in the nervous system

  
  

  Results in issues in memory, autism spectrum, and mental health disorders
• Contact-dependent signalling


  Signalling molecule remains bound to surface of signalling cell, it influences only cells that contact it

  
  

  It is very important in development, so communicating cells may send long cytoplasmic processes to contact each other
• Issues of contact-dependent signaling

  Can cause cells to differentiate into different cell types

  
  

  Can be used to promote apoptosis in cells

  
  

  Used in development of many tissues
• Paracrine signaling


  Signal released from a cell has an effect on neighboring cells.

  
  

  VERY common in development, important in organ induction

  
  

  It is secreted into the extracellular fluid

  
  

  For local activity

  
  

  Usually signalling and target cells are of different cell types
• Morphogen


  A growth factor, which diffuses between cells and has a different effect on a cell depending on its concentration
• FGF8


  It is expressed in the primitive streak, is important for migration of mesodermal cells

  
  

  Disruption of FGF8 (targeted) stops cell migration in gastrulating mouse embryo
• BMP4


  Required for development of primordial germ cells
• Sonic hedgehog (Shh)


  Key for nervous system, limb bud, gut and carniofacial structures
• WNT3a


  Mutations in humans can lead to tetra-amelia
• Tetra-amelia


  Lack of all four limbs, carniofacial, urogenital defects
• FGF receptor


  When normal, effects chondrocytes

  
  

  When mutated, growth plate becomes disorganised so no region of proliferating chondrocytes
• Do signalling pathways work alone?

  No - sometimes a mutation in one signalling factor results in mild effects. But when crossed with another single gene mutation in a different pathway, combination is generally lethal.
• What causes lineage specification and restriction of developmental potential?

  Totipotent cells of the epiblast differentiate

  
  

  More restricted in their developmental potential as gastrulation and embryogenesis proceeds
• When is implantation of the blastocyst?

  Day 9

  
  

  Before this, cell is just swimming around
• What controls the first cleavage division?

  RNA and things from the oocyte, before the zygote has control over things
• Establishment of asymmetry


  Anterior-posterior axis is formed, determined by the first cleavage

  
  

  The dorsal-ventral axis forms at right angles to the A-P axis
• Early implantation (day 6-8)

  Cells of the inner cell mass becomes epithelial like, and delaminate to form two layers
• Upper (dorsal) layer of inner cell mass

  Epiblast
• Lower (ventral) layer of inner cell mass

  Hypoblast
• Hypoblast


  Forms primitive endoderm that lines the yolk sack

  
  

  Gives rise to extra-embryonic
• Gastrulation


  Phase in the embryonic development of most animals, consisting of a complex and coordinated series of cellular movements
• Three germ layers


  Ectoderm

  Endoderm

  Mesoderm
• Endoderm


  the inner germ layer that develops into the lining of the digestive and respiratory systems
• Mesoderm


  the middle layer of an embryo in early development, between the endoderm and ectoderm.

  
  

  Reproductive tract, blood, muscle
• Ectoderm


  outermost germ layer; produces sense organs, nerves, and outer layer of skin
• The primitive streak


  Found on the surface of the epiblast

  The streak is vaguely defined initially, but is then clearly visible as a narrow groove

  
  

  Head end of the streak, the primitive node, consists of a slightly elevated area
• What is the beginning of gastrulation?

  Formation of the primitive streak
• What does mesoderm further develop into?

  Notochord, paraxial and lateral
• Disrupted gastrulation


  May be disrupted by genetic abnormalities and toxic insults

  
  

  Most are not survival, but sometimes they are