Download Elucidating Regulatory Networks in Nervous System Developmen

Elucidating Regulatory Networks in
Nervous System Development
• How do embryonic cells acquire
the ability to form
different regions of the
neural ectoderm?
• How are embryonic neural
stem cells established?
• Can this information be used
to direct ESCs to specific
neural fates in vitro?
Early Steps in Retinogenesis
1. Selection
Maternal of
VegT
Competent
and Vg1
inhibit
Progenitors
retina
2.Low
Selection
levels of
Retina-Biased
BMP signaling
Progenitors
• FGF3.signaling
prevents
Selection
of
• EphrinB1
signaling
Retinal Stem
Cellsvia
the PCP(eye
path
promotes
field)
4. Separation of
Eye Fields
NR
5. Regionalization
Into Neural and
Non-Neural
Progenitor Pools
Rx1 maintains
6. Neurogenesis
retinal stem
andcells
Pax6Determination
promotes celloftype
Restricted
biased
progenitor
Progenitors
cells
Neurotransmitter subtypes
of amacrine
cells
7. Cell
Type Differentiation
have different lineages
Steps in Central Nervous System Development
Neural
Induction
organizer
Noggin,
Chordin,
Follistatin
FGF, IGF
Stabilization
of Neural Fate
Neural
plate
Sox, Zic,
Iro, Gem
AnteriorPosterior
Axis
Regional
Identity
A
F
M
H
P
Sc
FGF,
Wnt
RA
Emx, Otx
FGF,En,Wnt
Krox, Hox
Shh/BMP
Cell Fate
Specification
bHLH genes
(Ash, Ngn,
NeuroD)
TFs involved in neural-fate stabilization
Organizer
Neural
Induction
Stabilization
early
late
Chordin
Noggin
Follistatin
Geminin
Siamois
Differentiation
Iro3
Ngn
Zic1, 3
Other
bHLH
factors
SoxD
Sox2, 3
Iro1, 2
Cerberus
Zic2
FoxD5
Ash
1. FoxD5 is expressed
in the early neural plate
10.5
3. FoxD5 loss-of-function
reduces the neural plate
Sox3 ISH
2. FoxD5 over-expression
expands the neural ectoderm
control
foxD5
100pg
foxD5
250pg
4. FoxD5 over-expression represses bHLH
differentiation genes
Proposed Gene Regulatory Pathway by which FoxD5
Represses the Onset of Differentiation
Sox3
FoxD5
Zic2
Zic1
Early-expressed
neural genes
Lateexpressed
neural genes
bHLH
factors
FoxD5 may be important for
maintaining neural plate
stem cells
FoxD5 also increases proliferation of embryonic cells
Embryonic origins of the vertebrate
nervous system
Neural plate:
Neural crest: Cranial ganglia
Spinal ganglia
Autonomic ganglia
Enteric ganglia
Cranial cartilage
Melanocytes
FoxD5
Neural
plate
CNS
Nc
Placodes:
Six1
Olfactory
Lens
Inner ear
Cranial ganglia
Secretory neurons
Lateral line
Initial induction of the pre-placodal ectoderm
(1) Six1 expression is activated by low levels of neural
inducers in the absence of Wnt and FGF signaling
(2) Six1 promotes a placode fate at the expense
of neural crest and epidermis
FoxD5
Neural plate
FoxD3
Neural crest
sox11, six2, six4, eya1
Six1
Placode
sox2, sox3, ngn1, neuroD
Foxi1
Dlx5,6
Epidermis
Six1 is involved in a GRN that establishes ectodermal domains
Six1 promotes early placode genes to establish fate and promotes cell
proliferation, but it represses differentiation genes
• FoxD5 is an upstream TF in the early
neural plate GRN
• Six1 is an upstream TF in the placode
GRN
• Both promote immature stem or
progenitor states by increasing
proliferation and repressing
differentiation genes
Petra Pandur (Six1)
Samantha Brugmann (Six1)
Tammy Awtry (Six1)
Himani Datta (Six1)
Melissa Davis (Six1)
Steve Sullivan (FoxD5)
Latania Akers (FoxD5)
Rakhee Goel (FoxD5)
Karen Neilson (Six1 & FoxD5)
Bo Yan (Six1, FoxD5, gene chips)
• Interactions between GRNs in the
different ectodermal domains
establish and maintain the
boundaries of these domains
• Understanding the GRNs that regulate
early neural fates will be
important for engineering cells
for tissue regeneration