Transcript If you can do anything, how to make sure you do the right thing at the

If you can do anything,
how to make sure you do
the right thing at the right time?
Stem cells, pluripotency, and
developmental timing in the embryo
Wolfgang Driever
FRIAS - Dec 1, 2010
http://www.decision-making-confidence.com/how-do-i-make-good-decisions.html
The act of making up your mind about something, or
a position or opinion or judgment reached after consideration
The process of selecting from several choices, products or ideas,
and taking action.
A simple decision making system
in 2D space and time
Decision making in time
state
naive
reversible
decision making
time
Information input into decision making
- generate structured decision patterns
Decision making in time
state
naive
reversible
decision making
with
spatial structure
time
information input
Problems
No stable decisions
Fuzzy pattern
Well defined
pattern
Stable and well defined pattern maintained
even in absence of continued information
What additional regulatory input
may be needed to achieve this
goal?
Decision making in time
state
open
state
pluripotent
reversible
decision
making
sharpening
decision
(integrate
info
over
time)
fixed
final
states
time
promote undecided state
repress decison
promote and fix decision
spatial information input
How do cells make such decisions
in real life?
The earliest cells in the embryo can
do anything.
They are pluripotent.
Mouse
Zebrafish
Human
Pluripotency and decision making in the embryo
3h
pluripotent
5h
deciding
12h
head
fate trunk
determined
tail
Decision making
time window
Pluripotency and decision making in the embryo
3h
pluripotent
spatial information
5h
deciding
12h
head
fate trunk
determined
tail
Brain - Neuroectoderm
Skin - Ektoderm
Muscle, Organs
Endo-Mesoderm
germ layers
Decision making in time
3h
state
open
state
pluripotent
12h
5h
reversible
decision
making
sharpening
decision
promote undecided state
Pou5f1/Oct4 “stem cell factor”
controls gene expression
spatial information input
fixed
final
states
time
How to investigate the temporal
sequential states during the
decision making process?
Determine temporal profiles of genes regulated by
Pou5f1:
Normal wildtypes compared to Pou5f1 mutants
Compare + Pou5f1 (wildtype) against - Pou5f1 (MZspg mutants)
pluripotency
lineage restriction
A large number of genes are not activated or
activated to abnormal levels in Pou5f1 mutants
1005 genes
reduced or absent
without Pou5f1
844 genes
increased in
without Pou5f1
An even larger number of genes is activated
prematurely or with delay: 7677 genes
delayed
prematurely
activated
hr
Pou5f1 targets - developmental regulators precisely
timed:
downregulated in MZspg
prematurely expressed in MZspg
downregulated in absence of Pou5f1:
Sox genes, many transcriptional repressors
prematurely expressed in absence of Pou5f1:
differentiation genes, promoters of differentiation
Effect of loss of Pou5f1 on
Decision making in time
3h
state
open
state
pluripotent
12h
5h
premature activation
reversible
decision
making
sharpening
decision
fixed
final
states
delay
promote undecided state
X
Pou5f1/Oct4 “stem cell factor”
controls gene expression
spatial information input
time