Transcript The Role of Natriuretic Peptides in Hearing

Upcoming Sessions
April 22: Nervous System Development Lecture
April 24: Reviews of Axonal Pathfinding in
Sensory Systems
April 29: Inner Ear Development Lecture
May 1:
Auditory System Pathfinding
Research Papers
May 6:
Reviews of Organ of Corti
Differentiation
May 8:
Hair Cell Differentiation Research
Papers
Inner ear development
Nervous system development
Nervous System Development
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Formation and differentiation of the
neural tube
Tissue architecture of the central
nervous system
Differentiation of neurons/generation
of neural diversity
Pattern generation in the nervous
system
Chick Embryo Whole Mounts
Primary Neurulation
(formation of neural tube)
Neural groove
MHP=medial hinge point
Primary Neurulation (cont’d)
Primary Neurulation (cont’d)
3 steps:
1. Formation of the neural plate
• Underlying dorsal mesoderm signals ectodermal cells to
elongate and form the neural plate (columnar cells)
2. Bending of the neural plate
• MHP cells become anchored to the notochord and change
shape forcing formation of the neural groove
• DLHP cells become anchored to the surface ectoderm
3. Closure of the neural tube
• Folds adhere to each other and cells merge
• In mammals, cranial neural crest cells migrate to the folds;
spinal NC cells don’t migrate until after closure
• Neural tube don’t close simultaneously (3 sites in mammals):
anterior neuropore closes first
• Separation from surface ectoderm occurs when neural tube
cells switch from expressing E-cadherin (like ectoderm) to
N-cadherin and N-CAM
Secondary Neurulation
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Mesenchyme cells coalesce into a solid
cord that subsequently forms cavities
that combine to form the hollow tube
Separately formed tubes join together
Occurs at transition regions at the
junctions of tubes formed via primary
neurulation
Nervous System Development
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Formation and differentiation of the
neural tube
Tissue architecture of the central
nervous system
Differentiation of neurons/generation
of neural diversity
Pattern generation in the nervous
system
Human Brain Development
Neural Stem Cells and
the Location of Dividing Cells
Cell Migration
After their terminal division, cells migrate
from the lumen toward the surface
Lamination
Cells with the earliest birthdays
migrate the shortest distances
Adult Stem Cells
Nervous System Development
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Formation and differentiation of the
neural tube
Tissue architecture of the central
nervous system
Differentiation of neurons/generation
of neural diversity
Pattern generation in the nervous
system
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Generation of neurons
Neural stem cells can become:
1. Ventricular (ependymal) cells: make CSF
2. Neurons: generate and conduct electrical
potentials
3. Glial cells: provide structure, insulate axons
Numbers are staggering:
o 1011 neurons associated with 1012 glia
o Each neuron forms as many as 100,000
synapses with 1,000 to 1,000,000 other
neurons
o Neurons can be separated from their targets
by distances of meters
Cell fate
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Neural vs. glial vs. epidermal fate is
determined by the Notch-Delta
pathway
o Inducing proteins are bound to the cell surface
o Cells expressing Delta, Jagged or Serrate
proteins activate adjacent cells that express
the Notch protein by causing a conformational
change that causes Presinilin-1 to cleave part
of the Notch intracellular domain
o Cleaved portion of Notch goes to the nucleus
and activates transcription factors
Neuronal type
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Determined initially by dorsal/ventral
position within the neural tube, which is
established by birthdate
Gradients of paracrine factors then cause
differential gene expression which
determines type (e.g., motor vs. sensory)
Early-born neurons can secrete retinoid
signals that alter gene expression of laterborn neurons as they migrate through to
their final position
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Dorsal/ventral
Specification
Eventually, in spinal cord
dorsal=sensory
ventral=motor
Ventral is specified by
notocord, via Sonic
hedgehog (Shh) 
converts MHC to become
floor plate  more Shh
Dorsal by ectoderm via
TGF-β  roof plate 
more TGF-β
Paracrine Factor Gradients
Motor neurons
(PNkx6.1 and Pax6 overlap)
Neurites
Growth Factors
Nervous System Development
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Formation and differentiation of the
neural tube
Tissue architecture of the central
nervous system
Differentiation of neurons/generation
of neural diversity
Pattern generation in the nervous
system
Specificity of Axonal Connections
3 steps:
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1. PATHWAY SELECTION: route to a specific
region
2. TARGET SELECTION: recognition of target
cells and formation of connections
3. ADDRESS SELECTION: refinement of
synapses so that each axon contects to a
small subset of its initial connections
First 2 steps are independent of
activity; final step often requires
synchronized electrical potentials
Pathway Selection
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Extracellular matrix proteins and growth
factors provide navigation cues to growth cones
ECM
(laminin vs. collagen)
Signalling molecules
(ephrins, semaphorin, netrin and Split)
Target selection
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Growth factors
released from
target tissues
act over very
short distances
to either attract
or repel axons
during their final
approach to the
target
Address Selection
(activity dependent refinement)
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Competition between axons for
innervation  less active synapses
are eliminated
Neuronal cell death
• Target tissue regulates the number
of axons innervating it via
neurotrophic factor concentration
• Neurons that lose their target
innervation die
Visual System Development
Central Auditory System Pathways