Download The Induction and Patterning of the Nervous System

The Induction
and Patterning
of the Nervous System
서울대학교 어린이병원 신경외과
왕규창
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
Organizer Region
 Spemann and Mangold
 amphibian embryos
 dorsal lip of blastopore, future dorsal
mesoderm
 transplantation: generated notochord,
induced second nervous system
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
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.
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
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
Holoprosencephaly
 fused cerebral hemispheres, especially
at the ventral area
 mutations in the human SHH gene
SHH Signaling Pathway
and Disease
 mutations in the human patched,
smoothened, and gli proteins
 spina bifida, limb deformities, cancer
Dorsal Induction
 BMP
 decapentaplegic in Drosophila
 BMP receptor
– transmembrane serine-threonine kinases
 SMADs (transcription factors)
phosphorylation
Common Principles in
Ventral and Dorsal Halves
 SHH vs BMP
 homeogenetic induction
– like begets like
– floor plate and roof plate
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
Rostrocaudal Axis
 forebrain: follistatin, noggin, chordin
 more posterior: FGF family protein
 hindbrain and spinal cord: retinoic acid
 patterning of the hindbrain
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
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
Retinoic Acid vs. Hox
 retinoic acid treatment: Hox gene
expression at more anterior level of the
hindbrain
 more posterior identity
 teratogenic and craniofacial abnormalities
Patterning of the Midbrain
 Hox gene expression (-)
 long-range action of signals from the
isthmus region (junction of mesencephalon-metencephalon)
 Wnt-1 and FGF8: regulates homeodomain
protein expression: engrailed 1 and 2
Forebrain Patterning
 6 prosomeres
 SHH: prosomeres 2 and 3
 Not all subdivisions of the telencephalon
develop independently.
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
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
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