Development & Evolution of Nervous Systems Genes Galileo: You cannot teach a man anything; you can...

Development & Evolution of Nervous Systems

Genes

Galileo: You cannot teach a man anything; you can only help him discover it himself.

Genes

fish neuromast fly bristle

Anticipate on next talk, about the fish lateral linemechanosensory system made of individual, superficial sense organs

called neuromasts

provides fish with a sense of touch-at-a-distance

cupula cells

support cell

sensory neuron

glial cell

hair cells

fish neuromast

cupula

shaft cell

fly bristle

shaft

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)

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 commonectodermal precursor cell through fixed lineage

mechanosensory organs

Fish Fly

support cells (=> external structure)sensory neuronsglial cellsmechanosensory hair cells + sensory neurons

support cells (=> external structure)sensory neuronsglial cellsmechanosensory neurons

Cellorganization

Origin

DevelopmentalGenetics

sensory cell fate depends onproneural gene

proneural gene expression leads to Delta expression

Cell types sorted out through Delta-Notch interaction

precursor fate depends onproneural gene

proneural gene expression leads to Delta expression

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

Aniridia eye illuminated from the back

Another example of conservation of sensory organ

normal human eye

eye of aniridia heterozygote

aniridia eye

lighted from behind

wild type

Heterozygote(reduced eye)

In mouse, there is a similar mutation, Small eye (Sey)

Sey- / Sey- homozygoteswild type

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)

The presence of a paired-box defines a family of genescalled Pax. The Pax genethat is affected in the Sey mutant is Pax6.

Paired-box codes for a DNA-binding protein motif called "paired-domain"

The Pax6 paired-box is highly conserved among animals(100% between mouse and man, 95% between man and fly)

vertebrate eye

arthropodeye

cephalopodeye

facet eye(large numberof ommatidia) 600 in the fly,

thousands in bees

camera-type cephalopod eyes resemble ours,

but similarityonly superficial

(orientation of retinais inversed)

=> at least 5 and arguably as many as 30 types of eyes evolved independently

wild type

ey- / ey-

wild type

the eyeless gene is the fly homolog of Pax6!

the eyelessmutation

Walter Gehring

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

arthropodeye

cephalopodeye

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??

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

The fly "eyeless" syntagm

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 embryohomologus to ventral side of arthropod embryo

=> The CNS of vertebrates and arthropods do occupy homologous positions

I

I

I

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In the fly embryo, slit (green) is expressed at ventral midline (red: muscle cell nuclei)+ plays important role in scaffolding

In vertebrate CNS, slit is expressed at ventral midline (by floor plate cells)

Development deals with topology

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?

Urbilat

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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?

30Myrs 500Myrs500Myrs

We don't know but... can we try to form a theory ?

Dickinsonia



Note: 610 - 550 myrs, Ediacaran (pre-cambrian ) fauna - England, Canada, Australia…



Mawsonites



Parvancorina - protoarthropod???







Tribrachidium (sym. 3)cnidarian-related?

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Charniodiscus (England, Australia, Russia, Canada…)

What happened to those? We have no idea…

What did developmental genetics tell us?

Why has basic structure of developmental programme been so strongly conservedto produce morphologies (and even functions) so drastically different?

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

1st rule : rule of conservative changes

given the complexity of the developmental program,

the only changes that can be accepted are those that change nothing

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

Conservation of interactions functional equivalenceof orthologous genes(pax6, otd, sc, Hox)

genetic inertiaof syntagms

of developmental operations few developmentalinnovations

ex: homeobox, the most conserved residues are those that ensurethe structural stability of the motif

ex: number of possible proteins = n20 for n ac. amino acids. Not true! internal constraints (foldability, stability...)

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

ex: psychology: new ideas or news are first screened for compatibilityscreen can become too rigid - autism

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

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

Mouse syndactily in Hoxa13 mutant

(defective apoptosis)

Human syndactily associated to mutations in Hoxd11,

(normally repressed by Hoxa13)

1. Hox code may help define the five digits

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!

2d rule : stability breeds variability

only robust pattern-generating system can withstand large variation without collapsing

1st rule: only conservative changes are toleratedany 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

Urbilat

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xx

30Myrs 500Myrs500Myrs

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)

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)

paradox:

within a few generations any species will adapt to selection (dogs, horses, flies)

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

3d rule: evolution depends on the survival of the misfits (tolerance)

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

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

Tolerance allows individuals to move away from the stable state to explore the neighbouring "evolutionary space"

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 yearsdivergence of Homo with closest primate : 2-4. 106 ans

series of hominid species, all quite short-lived, 105 à 4.105 yrsonly 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

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 developmentdid not appreciate how development is evolving

Massive extinctions that wipe out 80 - 95% of existing speciesaccompanied 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 increasedallows more risky explorations of evolutionary space with less efficient transitional types

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 itselfCannot 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

(end)

I know that you are going to applaud - and I think you are rightbut 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 cryingsame as African dancers, and also in South-America ritual dancing

that is because they were not themselves anymore, they were possessed - fate, gods, fortune, deathat 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, interpretersSo it is very well that you call me back among you now, please, clap your hands

Galileo, again: All truths are easy to understand once they are discovered;the point is to discover them

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 headMike 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 timesbut 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!"

Development & Evolution of Nervous Systems Genes Galileo: You cannot teach a man anything; you can...

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