Symmetry Breaking in Development

1
Symmetry Breaking in Development Dev Bio 4/24/06

• Lecture Outline
• Theoretical Foundation math, physics, chemistry
• Symmetry Breaking in AP and DV axis formation
• Left/Right Symmetry Breaking
• wmarshall_at_biochem.ucsf.edu

2

• Part I Theoretical aspects of symmetry breaking
• Terms - symmetry breaking self-organization
• Is symmetry breaking possible or impossible?
• Simple systems self-organize macroscopic
  structure
• Predicting macroscopic self-organization
• Turings reaction-diffusion theory
• 6. Key lessons from theory

3
Self-assembly
Ex crystals, viruses
Parts fit together only one way
Self-organization Symmetry Breaking
Ex clouds, dunes, embryos
Parts could go anywhere
4
Is spontaneous self-organization
possible? Organization decrease in entropy so
what about the 2nd law of thermodynamics?
matter, energy
matter, energy
B
A
DStotal gt 0 DStotal DSA DSB if DSA
gt DSB and DSA gt 0 then potentially DSB lt 0
5
Self organization CAN happen, but WILL it?
6
Example Knudsen Gas Experiment
nI TI
nII TII
Heat in
Heat out
nI nII TI TII
Transition to steady state
nI lt nII TI gt TII
DS -(1/16)(4Cv R)(DT/T)2 lt 0 !!!
Entropy not only CAN decrease, it MUST!
7
Macroscopic organization vs. microscopic ordering
Microscopic ordering but no Macroscopic morphology
Macroscopic-scale structure
Predicting which systems can form macroscopic
structure Prigogine Non-equilibrium
thermodynamics, stat mech Changes versus time
dynamical system Stability theory, qualitative
theory of dynamics (Thom, etc.)
Turing Formulate steady-state solution as
boundary value problem Solve in Fourier transform
domain - find wavelengths
8
Belousov-Zhabotinsky Reaction
Reaction scheme
Quote from a Biography of Boris Belousov Maybe
the first interest in chemistry arose in Boris'
mind when he together with his elder brother
tried to compose a bomb to kill the Czar. Making
bombs must be an interesting activity for
teenagers.
9
Bénard convection cells
10
Macroscopic organization vs. microscopic ordering
Microscopic ordering but no Macroscopic morphology
Macroscopic-scale structure
Predicting which systems can form macroscopic
structure Ilya Prigogine (de Groot,
Nicolis) Non-equilibrium thermodynamics, stat
mech Changes versus time gt dynamical
system Stability theory, qualitative theory of
dynamics (Thom, etc.)
Alan Turing (Gierer, Meinhardt) Formulate
steady-state solution as boundary value
problem Solve in Fourier transform domain - find
wavelengths
11
Turing Reaction-Diffusion Systems
Reactions within regions Diffusion between
regions Autocatalytic reaction - amplifies
fluctuation Diffusible inhibitor - reinforces
differences
Symmetry breaking can be biased by slight
pre-existing asymmetry
12
Local positive feedback diffusible inhibition
symmetry breaking
13
Local positive feedback diffusible inhibition
symmetry breaking
Bias asymmetry By local activation
14
Local positive feedback diffusible inhibition
symmetry breaking
Bias asymmetry By local protection
Self-organizing systems are easy to bias by
simple inputs
15
Turing Reaction-Diffusion Systems
Symmetry breaking can be biased by slight
pre-existing asymmetry
16

• Principles that the theory gives us
• Self organization is not only possible,
• in many cases it MUST occur.
• Self organization at a macroscopic spatial scale
  can be
• predicted by several theoretical approaches
• Self organization / symmetry breaking requires
  positive feedback
• but this is not sufficient. gt emergent
  property of system
• Self organization does NOT preclude instructive
  input
• (it actually makes it easier).

17
Symmetry breaking in early development
A
D
V
P
Asymmetry - transferred from mother vs.
spontaneous in embryo
18
Xenopus
cloud mitochondria mRNA (Xlsirt, Xcat2)
oocyte nucleus
19
Xenopus
Cloud and maternal pronucleus move randomly
20
Xenopus
21
Xenopus
22
Xenopus
23
Xenopus
Vegetal pole
Symmetry breaking by random placement of unique
mark
24
Xenopus - part II dorsal/ventral axis
Sperm entry
movement along microtubules
Dorsal determinants
MT array dictates dorsal position Centrosome
dictates MT direction What if there is no
centrosome?
V
D
25
Artificial activation of unfertilized Xenopus egg
movement along microtubules
MT array self-organizes Sperm centrosome is just
a bias
V
D
26
Ascidians
Weak spot
1st meiotic spindle
Sperm entry
dorsal
actin contraction
ventral
27
Ascidians
Weak spot
1st meiotic spindle
Sperm entry
dorsal
actin contraction
ventral
So does asymmetry arise from the meiotic spindle?
28
No visible weak spot
Sperm entry
dorsal
actin contraction
ventral
Actin cortex rips spontaneously to break
symmetry. Spindle biases it.
29
C. elegans
Sperm entry
A
P
So does mother pronucleus dictate AP axis?
30
Normal case
A
P
Displaced sperm entry
A
P
Paternal pronucleus (centrosome) dictates AP
axis. Symmetry breaking by a unique mark.
31
C. Elegans - how it works
Actin Myosin (NMY-2) PAR-3 PAR-6 PKC-3
PAR-2
Centrosome PAR-2 NMY-2
A
P
actin flow
32
C. Elegans - how it works
Actin Myosin (NMY-2) PAR-3 PAR-6 PKC-3
PAR-2
Centrosome PAR-2 NMY-2
Can the actin cortex break symmetry by itself?
A
P
actin flow
33
C. Elegans - how it works
Actin Myosin (NMY-2) PAR-3 PAR-6 PKC-3
PAR-2
Centrosome PAR-2 NMY-2
Can the actin cortex break symmetry by
itself? Centrosome can be ablated once Actin
flow begins.
A
P
actin flow
34
Drosophila - AP axis symmetry breaking
Polar follicle cells start out equivalent
Follicle cells
PFC
PFC
APFC Anterior polar follicle cells
PPFC Posterior polar follicle cells
Polar follicle cells at one end converted Into
special PPFC. - symmetry breaking PPFC provide
AP axis cue to oocyte
35
Drosophila - AP axis symmetry breaking
Nurse cells
oocyte
PPFC
36
Drosophila - AP axis symmetry breaking
Nurse cells
Follicle cells
oocyte
PFC
PFC
PPFC
PPFC
37
Drosophila - AP axis symmetry breaking
Nurse cells
Follicle cells
oocyte
PFC
PFC
PPFC
PPFC
So - position of oocyte converts PFC at one end
into PPFC
38
Drosophila - AP axis symmetry breaking
Nurse cells
Follicle cells
oocyte
PFC
PFC
PPFC
PPFC
gurken mRNA
gurken protein
PPFC state
Symmetry breaking by random juxtaposition of two
cell types
39
Gurken PPFC PKA MT reorganize
40
Oocyte nucleus migrates along random meridian to
break DV symmetry
gurken Nudel Toll Dorsal
41
Mechanisms of symmetry breaking of AP and DV
axes Cytoskeletal self-organization biased by
nucleus/centrosome Xenopus DV axis Ascidian DV
axis Nematode AP axis Unique mark without
cytoskeletal self-organization Xenopus
Animal-Vegetal axis Drosophila D/V axis Mollusc
d-blastomere (polar lobe) Random juxtaposition
of cells Drosophila AP axis mammalian DV
axis Whats missing here?
42
Mechanisms of symmetry breaking of AP and DV
axes Cytoskeletal self-organization biased by
nucleus/centrosome Xenopus DV axis Ascidian DV
axis Nematode AP axis Unique mark without
cytoskeletal self-organization Xenopus
Animal-Vegetal axis Drosophila D/V axis Mollusc
d-blastomere (polar lobe) Random juxtaposition
of cells Drosophila AP axis mammalian DV
axis Whats missing here?
Reaction-diffusion systems
43
Left-right symmetry breaking
normal
Situs inversus
44
(No Transcript)
45
nodal
lefty2
pitx2
Left-specific gene expression
46
nodal
lefty2
pitx2
Left-specific gene expression
47
nodal
lefty2
pitx2
Left-specific gene expression
48
nodal
lefty2
Autocatalytic activation of nodal Lefty2 is a
diffusible inhibitor of nodal
Does this remind you of anything?
49
Nodal/lefty network as possible
reaction-diffusion system
Dlefty2 gt Dnodal
nodal
lefty2
lefty2
lefty2
nodal
nodal
nodal
nodal
lefty2
lefty2
50
Pop quiz Nodal/lefty2 reaction-diffusion should
break symmetry randomly But our left side is
always on the left. So how can a
self-organizing system always break symmetry
in one particular way?
51
Pop quiz Nodal/lefty2 reaction-diffusion should
break symmetry randomly But our left side is
always on the left. So how can a
self-organizing system always break symmetry
in one particular way?
Answer - self-organizing symmetry breaking must
be BIASED by some upstream input
signal.
52
Kartageners syndrome 1. Chronic
bronchiectasis 2. Chronic sinusitis 3. Situs
inversus
53
(No Transcript)
54
iv/iv mutant mouse - 50 situs inversus.
iv Ciliary dynein Mutants that lack node
cilia (Kif3A, IFT88) - 50 situs inversus Why
is it always 50 situs inversus?
55
iv/iv mutant mouse - 50 situs inversus.
iv Ciliary dynein Mutants that lack node
cilia (Kif3A, IFT88) - 50 situs inversus Why
is it always 50 situs inversus?
Cilia bias left/right symmetry breaking by
nodal/lefty2
56
anterior
R
L
posterior
57
anterior
R
L
posterior
58
Flow is sufficient to dictate left/right symmetry
breaking
59
How does fluid flow influence nodal/lefty2
switching?
Morphogen sweeping
Mechanosensory cilia
60
Mechanisms of symmetry breaking during axis
formation Cytoskeletal self-organization biased
by nucleus/centrosome Xenopus DV axis Ascidian
DV axis Nematode AP axis Unique mark without
cytoskeletal self-organization Xenopus
Animal-Vegetal axis Drosophila D/V axis Mollusc
d-blastomere (polar lobe) Random juxtaposition
of cells Drosophila AP axis mammalian DV
axis Reaction-diffusion system biased by fluid
flow mammalian LR axis
61
(No Transcript)
62
(No Transcript)
63
(No Transcript)
64
(No Transcript)
65
(No Transcript)
66
(No Transcript)