Neural induction

• Neural Induction


  The process by which one embryonic region interacts with a second region to influence that second region's differentiation

  
• Neurons


  • Retain many common features throughout evolution of multi-cellular organisms (e.g. voltage gated ion channels, synaptic transmission)
  • Underlying principles of neural development have been maintained throughout evolution

  
• Embryonic development


  1. Egg cells are polarized with animal and vegetal poles

  2. Dorso-ventral axis generated after fertilization

  3. Fertilization, cleavage, multi-cellular blastula, gastrulation

  4. Gastrulation brings cells from surface to inside, generating ectoderm, endoderm and mesoderm layers

  5. Nervous system derived from ectodermal layer

  
• Gastrulation


  • Blastopore is the point of initiation
  • Dorsal side of blastopore is where first cells invaginate
  • Involuting marginal zone forms mesodermal tissues and induces overlying ectoderm to develop into neural tissue

  
• Neural plate formation


  1. Neural plate rolls up into a tube, fusing at dorsal margins and separating from ectoderm

  2. Notochord forms underneath neural plate

  3. Neural crest cells arise at junction between tube and ectoderm

  4. Neural tube cells give rise to neurons and glia

  
• Human embryo development


  1. Cleavage, blastula, inner cell mass forms embryo

  2. Primitive streak forms mesoderm

  3. Neural tube forms from ectoderm overlying involuting mesoderm

  
• Neural lineage


  Ectoderm cells become fated to generate neural tissue as a result of tissue rearrangements during gastrulation

  
• Spemann Organizer


  • Transplanted dorsal lip cells induce host ventral tissue to form neural tube and dorsal mesoderm
  • Organizes host and donor tissue into secondary embryo with A-P and D-V axes

  
• Induction


  The process by which one embryonic region interacts with a second region to influence that second region's differentiation
• Neural induction does not act solely through a vertical signal from involuting mesoderm

  
• Neural inducing signal can be passed through the plane of the ectoderm

  
• Extensive and patterned neural development occurs in cultures where mesoderm does not move inside but extends away from presumptive neuroectoderm

  
• The search for the neural inducer preoccupied scientists for decades after Spemann and Mangold's experiments
• Interactions between animal and vegetal cells are necessary for mesoderm induction

  
• Animal cap assays were used to study neural induction

  
• Noggin


  • A secreted protein identified through expression cloning that rescues the phenotype of UV ventralized embryos
  • Binds to and inhibits BMP2 and 4

  
• Chordin


  • A secreted protein expressed in the dorsal blastopore lip that, when overexpressed, gives rise to a secondary axis

  
• Follistatin


  • A secreted protein that binds to and inhibits activin, a TGF family protein
  • Inhibiting activin signalling in animal caps results in neural development
• The current model of neural induction in amphibian embryos is that neural inducers inhibit BMP4 signalling

  
• Neural inducers


  Inhibit BMP4 signalling
• Neural induction in amphibian embryos


  1. Deletion of one BMP antagonist - minor effects

  2. Deletion of 2 BMP antagonists - major effects on neural induction and development

  3. Antagonism of BMP signals via secreted BMP antagonists is clearly required for the development of much of the nervous system

  
• β-catenin


  Part of the Wnt signal transduction pathway

  
• β-catenin is necessary for forming the dorsal axis - experimental depletion of β-catenin transcripts results in lack of dorsal structures

  
• The injection of exogenous β-catenin into ventral side of embryos produces a secondary axis
• β-catenin


  Negatively regulated by the glycogen synthase kinase 3 (GSK-3)

  
• Wnt signalling pathway in Xenopus embryos


  1. β-catenin begins to accumulate in the dorsal region of the egg during the cytoplasmic movements at fertilization

  2. β-catenin continues to accumulate preferentially at the dorsal side throughout early cleavage and this accumulation is seen in the nuclei of dorsal cells

  
• β-catenin is initially synthesized throughout the embryo but is degraded by GSK-3 mediated phosphorylation

  
• Dishevelled protein


  Stabilizes β-catenin in the dorsal egg
• Siamois protein


  Critical for the expression of organizer specific genes

  
• Development of head structures and brain neural tissue requires the inhibition of the Wnt signalling pathway in addition to the BMP signalling pathway

  
• Wnt inhibitors


  • cerberus
  • frzB
  • dickkopf (dkk)
• Cerberus protein


  Has dual function in that it can inhibit both the Wnt and BMP pathways

  
• Co-inhibition of BMP and Wnt signals


  • Leads to induction of anterior neural structures, i.e. the brain

  
• Dkk1 knockout mice lack head and brain structures anterior to the hindbrain similar to the noggin/chordin knockout mice

  
• Synergy between the BMP antagonist noggin and the Wnt antagonist dkk1 can be seen in mice where a single allele of each gene is deleted - these mice have severe head and brain defects

  
• Sonic hedgehog


  Originates from the notocord and is necessary for the development on ventral neural tube fates
• TGF β proteins


  Originate in the dorsal ectoderm and are involved in dorsal-ventral specification of the neural tube

  
• Dorsal region of neural tube

  • Spinal neurons receive input from sensory neurons
• Ventral region of neural tube

  • Motor neurons form

  
• Middle region of neural tube


  • Numerous interneurons that relay information between sensory and motor neurons