Transcript Sey

Development & Evolution of Nervous Systems
Genes
Genes
Galileo: You cannot teach a man anything;
you can only help him discover it himself.
Anticipate on next talk, about the fish lateral line
mechanosensory system made of individual, superficial sense organs
called neuromasts
provides fish with a sense of touch-at-a-distance
fish neuromast
fly bristle
fish neuromast
fly bristle
cupula
shaft
hair cells
cupula cells
shaft cell
support cell
sensory neuron
glial cell
Cf Detlev Arendt in retina: evolutionary tendency to segregate different cell functions into different cell types
- allows cell specialization (segregation of rod, cones and bipolar cells; segregation of hair cells and neurons)
- allows amplification (many rods => one ganglion cell; many hair cells => one sensory neuron)
mechanosensory organs
Fish
Fly
Cell
organization
support cells
(=> external structure)
sensory neurons
glial cells
mechanosensory hair cells
+ sensory neurons
support cells
(=> external structure)
sensory neurons
glial cells
mechanosensory neurons
Origin
All cell types (incl. neurons)
originate from a common pool
of ectodermal precursor cells
long-range migration
All cell types (incl. neuron)
originate from a common
ectodermal precursor cell
through fixed lineage
Developmental
Genetics
sensory cell fate depends on
proneural gene
precursor fate depends on
proneural gene
proneural gene expression
leads to Delta expression
proneural gene expression
leads to Delta expression
Cell types sorted out
through Delta-Notch interaction
Cell types sorted out
through Delta-Notch interaction
If bristles and neuromasts are truly homologous,
their common features were probably present
before arthropods and chordates separated
Another example of conservation of sensory organ
normal human eye
eye of aniridia heterozygote
Aniridia
eye
aniridia
eye
illuminated from the back
lighted from behind
In mouse, there is a similar mutation, Small eye (Sey)
wild type
Heterozygote
(reduced eye)
wild type
Sey- / Sey- homozygotes
human homozygotes for the aniridia mutation also show anophtalmia
(absence of eyes) together with lethal cerebral alterations
Positional cloning of the gene affected in the Sey mutant:
the gene comprises a "paired-box"
(because first found in a pair-rule mutant called paired)
Paired-box codes for a DNA-binding protein motif called "paired-domain"
The presence of a paired-box
defines a family of genes
called Pax. The Pax gene
that is affected in the Sey
mutant is Pax6.
The Pax6 paired-box is highly conserved among animals
(100% between mouse and man, 95% between man and fly)
vertebrate
eye
camera-type
arthropod
eye
facet eye
(large number
of ommatidia)
600 in the fly,
thousands in bees
cephalopod
eye
cephalopod eyes
resemble ours,
but similarity
only superficial
(orientation of retina
is inversed)
=> at least 5 and arguably as many as 30 types of eyes evolved independently
wild type
the eyeless
mutation
wild type
ey- / ey-
Walter Gehring
the eyeless gene is the fly homolog of Pax6!
What will be the gain-of-function phenotype?
 forcing the expression of ey
in antennae and legs
(Gal4-UAS system)
Exactly same result is obtained using the mouse Pax6 gene
vertebrate
eye
arthropod
eye
cephalopod
eye
When you think about development,
take the point of view of the cells that make it,
not the point of view of the outsider who observes it
There are other mutations that reduce or remove the eyes:
eyes absent (eya)
eyes gone (eyg)
sine oculis (so)
eyeless-2 (ey2)
twin-of-eyeless (toy)
dachsous (dac)
Relations with Pax-6??
The fly "eyeless" syntagm
Not only Pax6 but many other genes of the « eyeless » network are conserved
in vertebrates where they also play a role in eye development
=> another case of sensory organ homology across all bilaterians
Olfactory system: cf Heinrich
Sensory systems may have been conserved,
but the central nervous system looks quite different!!!
=> inversion of dorso-ventral axis between protostomians et deuterostomians
such that dorsal side of vertebrate embryo
homologus to ventral side of arthropod embryo
=> The CNS of vertebrates and arthropods do occupy homologous positions
I
QuickTime™ et un
décompresseur TIFF (non compressé)
sont requis pour visionner cette image.
I
In the fly embryo, slit (green) is expressed
at ventral midline (red: muscle cell nuclei)
+ plays important role in scaffolding
I
Development deals with topology
In vertebrate CNS, slit is expressed
at ventral midline (by floor plate cells)
NOT with function
URBILATERIA
+ mechanosensory organs
+ olfactory system
+ synaptic asembly and plasticity
+ learning and memory
+ circadian rythm...
Cambrian explosion (530 - 500 Myrs ago)
nice: the conservation of genes and gene networks makes developmental genetics universal
In this "new" biology, nematode, fly, zebrafish, and man,
are just different expressions of a general programme for development
(provides a conceptual basis for the "model systems" approach)
also raises several (at least 3) serious questions:
in spite of infinitely diverse morphologies
development of all present-day animals based on the same very old genetic systems
Why?
Since they share the same old genetic systems
How do they form infinitely diverse morphologies?
500Myrs
30Myrs
500Myrs
Urbilat
x
x
x
x
One had to wait until the advent of a complex species
(in terms of structure and of developmental genetics)
before there could be any "evolution" (long-lived diversification)
Why?
We don't know but... can we try to form a theory ?
Note: 610 - 550 myrs, Ediacaran (pre-cambrian ) fauna England, Canada, Australia…
QuickTime™ et un
décompresseur TIFF (non compressé)
sont requis pour visionner cette image.
Dickinsonia
Mawsonites
QuickTime™ et un
décompresseur TIFF (non compressé)
sont requis pour visionner cette image.
QuickTime™ et un
décompresseur TIFF (non compressé)
sont requis pour visionner cette image.
QuickTime™ et un
décompresseur TIFF (non compressé)
sont requis pour visionner cette image.
Parvancorina - protoarthropod???
Tribrachidium (sym. 3)
cnidarian-related?
QuickTime™ et un
décompresseur TIFF (non compressé)
sont requis pour visionner cette image.
QuickTime™ et un
décompress eur TIFF (non c ompres sé)
sont requis pour v is ionner cette image.
Charniodiscus
(England, Australia, Russia, Canada…)
QuickTime™ et un
décompress eur TIFF (non c ompres sé)
sont requis pour v is ionner cette image.
QuickTime™ et un
décompresseur TIFF (non compressé)
sont requis pour visionner cette image.
What happened to those?
We have no idea…
Why has basic structure of developmental programme been so strongly conserved
to produce morphologies (and even functions) so drastically different?
What did developmental genetics tell us?
Conclusions of the work on fly bristles :
1. Developmental processes result from the concatenation of
discrete, qualitatively different steps
2. Each step depends on a small network of interacting genes
(a syntagm)
developmental genes embedded in complex network of interactions
any change will first be screened for its compatibility with network:
coherence must be maintained
as more interactions, number of degrees of freedom smaller:
changes will be more and more constrained
given the complexity of the developmental program,
the only changes that can be accepted are those that change nothing
1st rule : rule of conservative changes
Conservation of interactions
of syntagms
of developmental operations
functional equivalence
of orthologous genes
(pax6, otd, sc, Hox)
genetic inertia
few developmental
innovations
rule of conservative changes valid for all biological systems
Any change in a structure is screened
for its compatibility with the other elements
the absolute requirement is to keep the coherence
ex: homeobox, the most conserved residues are those that ensure
the structural stability of the motif
ex: number of possible proteins = n20 for n ac. amino acids. Not true!
internal constraints (foldability, stability...)
ex: psychology: new ideas or news are first screened for compatibility
screen can become too rigid - autism
ex: brain: any change is screened for its compatibility with existing connectivity
(ex: auditory projection vs lateral line projection)
Because of the nervous system's complexity,
requirement for internal coherence may
have been most pronounced in this system
Problem: if developmental program so resistant to change, how can it evolve?
(cf Ian's wild variations of nervous systems:
range of 106 in numbers of neurons, of 103 in synapses/neurons,
yet each of them perfectly suited to its owner's needs, and ensures long-term survival)
By changing the connectivity between syntagms
interactions within a syntagm: many and often bidirectional
interactions between syntagms: limited and usually unidirectional
Examples
reiteration : many examples in wiring of embryonic CNS
temporal change (heterochrony, neoteny)
spatial change : pigmentation patterns
Spatial change may have important developmental consequences
By changing the connectivity between syntagms
By new use of old syntagm: use of Hox genes in the limbs of vertebrates
Hox genes re-expressed during limb formation
1. Hox code may help define the five digits
Human syndactily
associated to mutations in Hoxd11,
(normally repressed by Hoxa13)
Mouse syndactily
in Hoxa13 mutant
(defective apoptosis)
Hexadactyly:
never six different fingers (always 5 fingers + 1 duplicate)
2. Hox code makes
different sections of limb
genetically different
once the limb program has become very robust
(because relies on the Hox system?)
can withstand wide morphological variations
but necessarily based on a five fingers pattern!
1st rule: only conservative changes are tolerated
any addition that does not alter a process will be accepted
(redundant genes, redundant mechanisms, redundant factors)
example: both pre- and post-synaptic elements can initiate synapse formation (Bill Harris)
L1 and L2 pathway mediate redundant or cooperative response depending on light conditions (Ian)
=> long term tendency to stabilize any developmental process
because only compatible « plug-ins » can accumulate and further stabilize the process
example: many more proteins involved in synapse stabilization than in transmission! (Bill Harris)
« canalization » (Waddington)
Once a developmental process has become extremely robust,
can withstand wide variations without collapsing
example: the five digits of the hand, common to all tetrapods, possibly related to Hox gene coding
2d rule : stability breeds variability
only robust pattern-generating system can withstand large variation without collapsing
500Myrs
30Myrs
Urbilat
x
x
x
x
500Myrs
SUMMARY SO FAR
Developmental genes embedded in complex network of interactions
their function depends on this network
the only changes that can be accepted are those that do not change anything
(1st rule : rule of conservative changes)
=> genetic inertia (cannot modify the building blocks)
Once a developmental process has become extremely robust,
can withstand wide variations without collapsing
only those developmental programs that are very stable can vary
(2d rule : stability breeds variability)
=> evolvability (if not stable enough, cannot change)
paradox:
within a few generations any species will adapt to selection (dogs, horses, flies)
therefore any species optimally adapted to its environment
(Heinrich Reichert: the shark's brain is exactly what you need if you are a shark)
=> departure from "normal" (species-specific) pattern will be detrimental
conclusion: speciation will necessarily proceed through less adapted individuals
will depend not on adaptation to the environment
but on tolerance of the environment
3d rule: evolution depends on the survival of the misfits (tolerance)
classical view : evolution depends on selection of the fittest
developmental view: selection allows the optimization of a species
tolerance allows the formation of new species
Tolerance allows individuals to move away from the stable state
to explore the neighbouring "evolutionary space"
If there is some tolerance,
a less efficient variant can be maintained in the population (at least for a while)
may get associated to another variation that may somewhat compensate
=> succession of transient, unstable forms
that accumulate compensatory changes to recover lost coherence
Once a subpopulation has derived too far away from the starting, stable solution (species)
succession of unstable, short-lived, transitional types (short-lived "species")
until hopefully hits a new coherent, stable state
= a new species
Ex: human evolution
standard lifespan of a species: 4.106 years
divergence of Homo with closest primate : 2-4. 106 ans
series of hominid species, all quite short-lived, 105 à 4.105 yrs
only one remaining at the moment, sapiens, appeared about 2.105 yrs ago
strongly suggests a number of poorly coherent short-lived species
live just long enough to generate next attempt
until eventually new equilibrium will be reached, or attempt will have failed
Massive extinctions that wipe out 80 - 95% of existing species
accompanied by wide expansion of new species
(e.g. the expansion of mammals related to the extinction of dinosaurs)
(??? Cambrian explosion related to extinction of ediacaran fauna???)
Possibly because tolerance much increased
allows more risky explorations of evolutionary space
with less efficient transitional types
Not meaning that Darwin was wrong!!!
(he was concerned about the problem of the Cambrian explosion)
He did not know what we know today about genes and development
did not appreciate how development is evolving
The end
(beginning)
Course about development and evoln of NS know a lot about NS, genes: excitability (channels), transmission (synapses, transmitters), signaling (plasticity)
A lot about dev, steps, gene networks - v little about evol (on principle act on genes; besides that: v little)
Oh yes comparative neuroanat, comparative embryol: end result of evo - tells nothing about evo itself
Cannot teach you anything - not too bad bec Galileo said What I will do is to review with you some of the things we learned so far about evoln and genes and dev
And try to see if we can form hypotheses, or at least find a way to look at these problems that makes sense
Galileo, again: All truths are easy to understand once they are discovered;
the point is to discover them
(end)
I know that you are going to applaud - and I think you are right
but I also think that you do not know why - I 'll tell you
In the old times, 2500 years ago, greeks were playing tragedies - often wore masks, smiling of crying
same as African dancers, and also in South-America ritual dancing
that is because they were not themselves anymore, they were possessed - fate, gods, fortune, death
at the end the public would clap their hands to get them out of their trance
clapping the hands meant "come back now, you who are possessed, come back to us"
I think that when we teach something similar happens - less intense, of course
we are not ourselves, we are just servants, tools, interpreters
So it is very well that you call me back among you now, please, clap your hands
Mike, Heinrich, Ian, Matthews Matthews (Indian) feel exactly what I say about "possessed"
even students seem to undersatnd it, at least some of them - clapping their hands high next to head
Mike wonders how it is that I always get something highly unusual but true to say
(last time: Easter's curve of attention - Vijay took a copy of it, remembers it so vividly!
Coffee after talk, Mike: "I won't say anything about your talk because you do not want to listen anyway"
"I always feel privileged to listen to you"
Heinrich: it all makes so much sense,
I saw the succession of human species in textbooks many times
but never made sense of it!
Next day: about marine station near Bangalore,
Mike: "I always wanted to look at some transparent marine animal"
Me: "why didn't you do it?" he: "I got distracted" me: "that would be a good epitaph to put on our tombstones"
He: right, "sorry, I got distracted!"