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Differentiation of the Neural
Tube
Gilbert - Chapter 12
Today’s Goals
• Realize that Nervous system is
patterned on A-P and D-V axis
• Describe mechanisms by which this
pattern is set-up
– Identify important signaling pathways
involved
Ectoderm
• Surface Ectoderm:
– Epidermis, hair, nails, olfactory epithelium, mouth
epithelium, tooth enamel, lens, cornea
• Neural Crest:
– PNS (sympathetic and parasympathetic), adrenal
medulla, melanocytes, facial cartilage, dentine of
teeth
• Neural Tube:
– Brain, neural pituitary, spinal cord, motor neurons,
retina
Differentiation of Neural Tube
• The actual gross morphological
changes, making each portion of the
neural tube special
– Specialized on A-P axis
– Specialized on D-V axis
– Specialized cell types form
• Neurons, glia, neural tissues (brain, spinal
cord)
Neural Tube Differentiation
• Differentiation into various regions of the CNS
• Happens in 3 ways, simultaneously
– Gross anatomical changes - bulging and
constriction of Neural tube to form chambers of
brain and Spinal Cord
– Tissue-level Changes - Cells rearrange into
functional regions of the brain
– Cellular-level Changes - Cells differentiate into
various neural cell types
• Neurons (nerve cells)
• Glia (supporting cells)
The A-P Axis of the Nervous
System
• The anterior portion of Neural tube is
organized into various regions along the
A-P axis (Will form regions of the brain)
• Early Neural Tube
– Forebrain (Prosencephalon)
– Midbrain (Mesencephalon)
– Hindbrain (Rhombencepalon)
Anterior-Posterior Neural specialization: mammalian brain See figure 12.9
A-P axis
• Controlled by a variety of genes
– Those expressed during gastrulation
• Chordin, noggin, etc.
– Hox genes - give global A-P identity
• We’ll discuss further later in the semester
Dorsal-Ventral Neural
Patterning
• Dorsal spinal cord - sensory neurons
• Ventral spinal cord - motor neurons
– What’s the difference?
• Interneurons
– Relay info between the above
• ***D-V polarity of neural tube relies on signals
from the notochord (mesoderm) and overlying
ectoderm (epidermis)***
Ventralizing Signals
• A signaling molecule is released from
the notochord
• SHH induces the ventral neural tube to
become “floor plate”
– This induces the floor plate to secrete SHH
– Result is a gradient of SHH expression
from ventral to dorsal
Expression of SHH mRNA in a
4 day old Chick embryo
SHH
• Member of the Hedgehog Family of
Proteins
• Example of “Paracrine” signaling
• Used in many places during embryonic
development to influence cell fate
How does it work?
(a simplified look)
• SHH is released from a inducer cell
• Binds to its receptor -Patched protein
– On the surface of nearby responder cell
• This causes a second protein Smoothened - To become activated
• Causes Phosphorylation of “Fused”
protein
• Activation of a transcription factor that
turns on expression of new genes
Hedgehog Intracellular
Signaling Cascade
SHH
• Also important in:
– Somite Development
– Limb Development
– Neural Differentiation
– Mutants in SHH have drastic phenotypes,
including Cyclopia
Ex. Of Cyclopia in a Lamb
(Not a SHH Mutant)
Dorsalizing Signals
• Overlying ectoderm secretes proteins in the
TGF-ß family of proteins (Transforming
growth factor)
– BMP’s (bone morphogenetic protein)
• BMP4, BMP7
• This induces the dorsal neural tube to form
the “roof plate”
– Roof plate begins to express BMP4 protein
– Again a gradient of expression is established
TGF-ß Signaling Pathway
• Ligand (Ex. BMP-4) Binds to receptor
– Receptors are Heterodimers
– Transmembrane proteins
• When ligand binds, triggers cascade of
phosphorylation events
• Phosphorylates SMAD4 transcription factor
• Enters nucleus and activates gene
expression
Gradients Set up Unique Cell
Identities
• Depending on signals received, cells turn on
different transcription factors
• Cells that receive high levels of SHH
– Turn on Nkx6.1, Nkx2.2
– Become ventral neurons
• Cells that receive less SHH and more TGFß’s
– Turn on Nkx6.1, Pax6
– Become motor neurons
Each Cell gets its own
address!
Dorsalin (TGF-ß
family)
Motor neurons
Sonic Hedgehog
Notochord/Sonic Hedgehog
Protein
• Necessary for ventral floor plate cell
formation
– Remove notochord, no floor plate cells!
• Notochord, and particularly SHH are sufficient
to induce floor plate
– Notochord transplant can induce ectopic floor
plate
– Pellet of cells that express SHH induce ectopic
floor plate
– 2nd floor plate makes 2nd set of motor neurons
Dev. Of Human Spinal Cord
Adult Neural Stem Cells
• Until recently - believed we could not
replace neurons after the first few years
of life
• Recent studies suggest that adult
mammalian brains are capable of
producing new neurons
• Studies in rats, other mammals
Adult Neural Stem Cells
• Post-mortem studies of patients treated
injected with a chemical that traces new cell
division (marker for cancer cells, and any
other cell that is dividing)
– Showed NEW neurons, although FEW
• Well established for some regions of the brain,
controversial in others (cortex)
• How they are maintained is not well understood
Xenopus Neurulation Lab
• Examine stages of Xenopus undergoing
neurulation
– 4 Stages
– Draw what you see and label:
•
•
•
•
•
Neural Plate
Neural Groove
Neural Folds
Neural Tube
15 points - Lab Activity Grade