Download Fate specification and patterning

How to generate a complicated organism?
Fate specification and
patterning
Shen-Ju Chou
ICOB, R333
2789-9530/[email protected]
But, actually…
1.  During cell
divisions, cells
somehow
become
different from
one another.
2.  The initial cell
asymmetries
subsequently
lead to
changes in
gene
expression and
change cell
fate.
Patterning: Generating a pattern
After neural induction….
How to generate a functional nervous system
--The inductive signals play major roles in pattern formation
A
V"
P"
D"
D"
P
Hox genes: assign identity to a segment
Formation of the brain regions:
Highly"conserved"Hox"
genes:"AP"pa8erning"
•  Duplica:on"of"gene"
clusters"
•  Expressed"in"an"
overlapping"series"of"
domains"along"the"AP"
axis"
•  The"order"of"expression"
corresponding"to"the"
gene"order"in"the"cluster"
?
The Generation of the Forebrain
Lim1J/J"
The induction of forebrain
PreJearly"gastrula:on"
AQer"gastrula:on"
(Brewster"and"Dahmane,"1999)"
e.g."BMP/Wnt"atagonist:"cerberus,"dkk"
(Shawlot"and"Behringer,"1995)"
Patterning the forebrain
D-V patterning of Cerebral Cortex
Dorsal fate: Pax6, Sox6…
dTel: cortical projection neurons
Is required for ventral cell fates
vTel:
•  MGE: projection neurons of the pallium
and basal forebrain and cortical
interneurons
•  LGE: projection neurons of the striatum
and interneurons in the olfactory bulb
Patterning of the forebrain
Different regions in the cortex:
Specific location and connection
A/P"
D/V"
Domains with specific functions
A-P patterning of Cerebral Cortex
Morphogens"
Patterning of the cortex by Fgf8
Graded"expression"of"genes"
Forma:on"of"boundaries"
Graded expression of transcription factors and area patterning
Morphogens
Gradient-expressed genes in the dTel determine
cortical neuronal fate
A"
P"
M"
S1"
V1"
Emx2
Coup-TFI acts to repress within its expression
domain frontal/motor identities allowing for
specification of sensory areas
Size matters: but bigger might not be better
CoupJTF1"cKO"
WT"
COUPJTF1"
(Armentano,"Chou,"et"al,"
Nature"Neuroscience"2007)"
COUP-TF1 normally represses motor area identities, "
allowing for proper patterning of sensory areas"
(Tomassy"et"al,"PNAS"2010)"
•  There"is"an"ideal"size"for"each"func:onal"domain"
Patterning of the neuroectoderm
Graded expression of TF in the dTel determines
cortical neuronal fate
A"
•  Through patterning mechanisms, the nervous system is
differentiated into specialized regions/areas.
•  Patterning is initiated by graded signals (morphogens)
that regulate discrete domains of gene expression along
an axis (A-P or D-V).
•  Finer scaled patterning occurs within the initial broad
domains and this often involve setting up of new
signaling centers at domain borders.
P"
M"
S1"
?
Emx2
?
V1"
Generation of the
diversity of cortical
neurons
1. 
2. 
3. 
4. 
Neuronal specification: Neurogenesis
Neuron/Glia
Neuronal types (excitatory or inhibitory)
Area determination
Layer determination
Potency of neural progenitors
Controlled by extracellular signals
The regulation of proliferation and differentiation
prolifera:on"
differen:a:on"
Control the number and
the diversity of neurons
Generation of layer-specific identity
Nctx"
The 6 layers of cortical neurons
Hp"
Allen Institute for Brain Science"
Generation of cortical layers: inside out
The 6-layer neocortex is a newly evolved brain
structure"
Mouse
Reptile
Cortical Neurogenesis: multiple progenitor types
Regulation of cortical progenitor division
Intermediate"Progenitor"Cells"
Radial"Glia"Cells"
Neuroepithelial"Cells"
Neurons
Progenitors
Cortical size control: brain evolution and disease state
Evolu:on"of"the"brain"
Microcephaly
Variation in brain size and patterns of convolutions
Progressive restriction in fate determination
Potency of neural progenitors
L6"
L2/3"
L4"
Decrease"over":me"
Specification of cortical neurons
Different types of
neurons in the cortex:
Laminar markers
Fezf2&
Satb2&
Neurons in different layers:
•  Different structure
•  Different connection
•  Different gene expression profile
Specification of cortical neurons
How to generate different neurons?
--multiple progenitor types in developing cortex
*"
*&
Different"neuronal"types"can"be"generated"from:"
•  Different"cor:cal"progenitors""
•  Different"subpopula:on"of"cor:cal"progenitors"
"
How does birth date influence a neuron’s fate?
How does birth date influence a neuron’s fate?
Regulated by intrinsic factors
Progenitor"cells"in"the"neural"tube"generate"different"neural"cells"over":me:"
Intrinsic mechanism of temporal control in neuroblasts in Drosophila CNS
•  Neuroblasts"express"different"transcrip:on"factors"as"they"divide."
•  Each"TF"confers"a"different"iden:ty"of"ganglion"mother"cell."
•  Expression"of"TFs"is"regulated"by"an"intrinsic"“clock”."
Combinational control by transcription factors generate neural diversity
Molecular"switch"
Transcriptional regulation of downstream genes
bHLH"
LIMJHD"
Synergis:c"interac:on"
*"
Intrinsic control of temporal cortical neurogenesis
(Lancaster,"2013)"
(Gaspard"and"Vanderhaeghen,"2011)"
Patterning of the cortex: to generate
the diversity of cortical neurons