The Induction and Patterning of the Nervous System

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The Inductionand Patterning of the Nervous
System

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Factors Determining Gene Expression

• inducing factor
• receptor ? transcription factor
• competence ability of the cell to respond to
  inductive signals
• determined by the repertory of receptors,
  transduction molecules and transcription factors

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Organizer Region

• Spemann and Mangold
• amphibian embryos
• dorsal lip of blastopore, future dorsal mesoderm
• transplantation generated notochord, induced
  second nervous system

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Neural Induction

• default state of the ectoderm
• dissociated single cell without intercellular
  signaling neural cell
• suppressor of neural differentiation BMP
• abnormal BMP receptor neural differentiation

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BMP Blockade

• Xenopus ectoderm
• organizer region
• endogenous neural inducers
• follistatin, noggin, chordin
• Neural differentiation by inhibition of BMP
  signaling involves transcription factors of the
  Sox gene family.

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Sonic Hedgehog (SHH)

• as an inducer both necessary and sufficient for
  the induction of most cell types in the ventral
  half of the neural tube
• as a morphogen directs different cell fates at
  different concentration thresholds

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Sonic Hedgehog (SHH)

• synthesized as an inactive precursor cleaved to
  be active
• addition of cholesterol molecule
• tether most of SHH to the surface of notochord
  and floor plate cells
• permits diffusion of small amount

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Holoprosencephaly

• fused cerebral hemispheres, especially at the
  ventral area
• mutations in the human SHH gene

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SHH Signaling Pathwayand Disease

• mutations in the human patched, smoothened, and
  gli proteins
• spina bifida, limb deformities, cancer

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Dorsal Induction

• BMP
• decapentaplegic in Drosophila
• BMP receptor
• transmembrane serine-threonine kinases
• SMADs (transcription factors) phosphorylation

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Common Principles in Ventral and Dorsal Halves

• SHH vs BMP
• homeogenetic induction
• like begets like
• floor plate and roof plate

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Signals for Brain Patterning

• SHH dopaminergic neurons of the substantia nigra
  and ventral tegmental area
• forebrain BMP signals were translocated from
  dorsal to ventral distinctive cell types in the
  forebrain

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Rostrocaudal Axis

• forebrain follistatin, noggin, chordin
• more posterior FGF family protein
• hindbrain and spinal cord retinoic acid
• patterning of the hindbrain

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Hox Gene Cluster

• Homeobox genes
• 180bp, encodes homeodomain
• four separate chromosomal complexes or clusters
• derive from a common ancestral Hox complex
• mutations homeotic transformation
• HOM-C in Drosophila

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Hox Gene Cluster

• homeodomain
• encoded by homeobox genes
• highly conserved 60 a.a. DNA binding domain
• transcription factors
• control of rhombomere(segmentation) identity in
  hindbrain

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Retinoic Acid vs. Hox

• retinoic acid treatment Hox gene expression at
  more anterior level of the hindbrain
• more posterior identity
• teratogenic and craniofacial abnormalities

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Patterning of the Midbrain

• Hox gene expression (-)
• long-range action of signals from the isthmus
  region (junction of mes- encephalon-metencephalon)
  
• Wnt-1 and FGF8 regulates homeodomain protein
  expression engrailed 1 and 2

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Forebrain Patterning

• 6 prosomeres
• SHH prosomeres 2 and 3
• Not all subdivisions of the telencephalon develop
  independently.

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Forebrain Patterning

• Some neurons in neocortex are from striatal
  subdivisions.
• striatal progenitors
• homeodomain proteins Dlx-1 and 2
• mutations failure of striatal progenitors to
  migrate into the neocortex, marked depletion of
  GABA neurons

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Cortical Differentiation

• afferent input
• somatosensory cortex experiment
• barrels in the rodents
• organization of whisker field
• intrinsic programs of cell differentiation
• lac-Z transgenic mouse experiment

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Economy in Development

• small number of inducing factors
• conserved signaling molecules, receptors,
  developmental programs throughout animal
  evolution
• combination of genes for segmentation
• same processes at different developmental stages