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The Induction and Patterning of the Nervous System

The Induction and Patterning of the Nervous System. 서울대학교 어린이병원 신경외과 왕 규 창. Factors Determining Gene Expression. inducing factor receptor  transcription factor competence: ability of the cell to respond to inductive signals

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The Induction and Patterning of the Nervous System

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  1. The Inductionand Patterning of the Nervous System 서울대학교 어린이병원 신경외과 왕 규 창

  2. 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

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

  4. 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

  5. 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.

  6. 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

  7. 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

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

  9. SHH Signaling Pathwayand Disease • mutations in the human patched, smoothened, and gli proteins • spina bifida, limb deformities, cancer

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

  11. Common Principles in Ventral and Dorsal Halves • SHH vs BMP • homeogenetic induction • like begets like • floor plate and roof plate

  12. 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

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

  14. 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

  15. 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

  16. Retinoic Acid vs. Hox • retinoic acid treatment: Hox gene expression at more anterior level of the hindbrain • more posterior identity • teratogenic and craniofacial abnormalities

  17. 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

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

  19. 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

  20. 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

  21. 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

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