動(dòng)物身體圖式的模式建成

動(dòng)物身體圖式的模式建成第1頁/共63頁All

vertebrates,

despite

their

many

outward

differences,第2頁/共63頁have

a

similar

basic

body

planThe

skeleton

of

a

mouse

embryo

illustrates

the

vertebrate

body

planThe

AP

axis:head,trunk

with

pairedappendages(vertebral

column脊柱)and

thepost-anal

tailThe

vertebral

column

is

divided

into

cervical

(neck),thoracic

(chest),

lumbar

(lower

back),

and

sacral

(hipand

lower)

regionsThe

DV

axis:

the

mouth

defining

the

ventralside

and

the

spinal

cord

the

dorsal

side第3頁/共63頁P(yáng)atterning

the

body

plan

in

vertebrates第4頁/共63頁Early

development

in

Drosophila

is

largely

under

the

control

ofmaternal

factors

that

sequentially

activate

a

different

sets

of

theembryo’s

own

genes

(zygotic

genes)

to

pattern

the

body

plan.Vertebrate

axes

do

not

form

from

localized

determinants,

as

inDrosophila.

Rather,

they

arise

progressively

through

a

sequence

ofinductive

interactions

between

neighboring

cells.

Amphibian

axisformation

is

an

example

of

this

regulative

development.The

experiments

of

Hans

Spemann

and

his

students

showed

thereexists

an

embryonic

organizer,

Spemann

organizer

that

determines

theamphibian

axis

formation

and

patterns

the

embryo

along

the

body

axes

through

inducing

such

inductive

interactions.Patterning

the

body

plan

in

animals第5頁/共63頁Development

of

the

Drosophila

body

planSpecification

of

the

antero-posterior

and

dorso-ventral

axis

in

DrosophilaoocyteSetting

up

the

body

axes

in

DrosophilaPatterning

the

Drosophila

embryoPatterning

the

vertebrate

body

planSpecification

and

setting

up

of

the

body

axes

in

amphibians

(Xenopus)Somite

formation

and

antero-posterior

patterningPatterning

the

vertebrate

nervous

systemSpecifying

the

left-right

axis

(left-right

asymmetry

of

internal

organs)In

the

transplantation

experiments,

Hans

Spemannand

Hilde

Mangold

showed

that

the

dorsal

lip

of

theblastopore

can

induce

the

host’s

ventral

tissues

toform

a

second

embryo

with

clear

antero-posteriorand

dorso-ventral

body

axes.

Spemann

refered

thedorsal

lip

as

the

organizer.第6頁/共63頁The

discovery

of

the

Spemann

organizerDr

Hans

Spemann---the

Nobel

Laureate

in

Physiology

or

Medicine

1935For

his

discovery

of

the

organizer

effect

in

embryonic

development第7頁/共63頁Mechanisms

underlying

role

of

the

Spemann

organizer

indevelopment

of

the

body

plan第8頁/共63頁How

was

the

organizer

specified

and

formed?

What

caused

the

dorsalblastopore

lip

to

differ

from

any

other

region

of

the

embryo?What

factors

were

being

secreted

from

the

organizer

to

create

theantero-posterior

and

dorso-ventral

axes?How

did

the

patterning

of

the

embryo

along

the

body

axes

becomeaccompanied?Mechanisms

underlying

role

of

the

Spemann

organizer

indevelopment

of

the

body

plan第9頁/共63頁How

was

the

organizer

specified

and

formed?

What

caused

the

dorsalblastopore

lip

to

differ

from

any

other

region

of

the

embryo?What

factors

were

being

secreted

from

the

organizer

to

create

theantero-posterior

and

dorso-ventral

axes?How

did

the

patterning

of

the

embryo

along

the

body

axes

becomeaccompanied?The

developmentally

important

maternal

factors

are

differentiallylocalized

along

the

animal-vegetal

axis

in

the

Xenopusunfertilized

eggs第10頁/共63頁The

Xenopus

egg

possesses

a

distinctanimal-vegetal

axis,

with

most

of

thedevelopmentally

important

maternalproducts

(mRNA/proteins)

localized

in

the

vegetal

regionVg-1

is

a

member

of

TGF-betafamily

of

signaling

proteins第11頁/共63頁The

cortical

rotation

upon

sperm

entry

can

both

specify

thedorsal

side

of

the

amphibian

embryo,

and

induceformation

of

the

Spemann

organizer第12頁/共63頁The

cortical

rotation

relocates

those

maternal

factors

,

such

as

Wnt-11

and

Dishevelledprotein

originally

located

at

the

vegetal

pole

to

a

site

approximately

opposite

to

the

spermentry.

These

factors

called

dorsalizing

factors

specify

their

new

location

as

the

future

dorsalside

of

the

embryo,

thus

conferring

the

dorsal-ventral

axis第13頁/共63頁Model

of

the

mechanism

by

which

the

Disheveled

proteinstabilizes

beta-catenin

in

the

dorsal

portion

of

theamphibian

egg第14頁/共63頁The

role

of

Wnt

pathway

proteins

in

dorsal-ventral

axisspecification(I)第15頁/共63頁E:

Blocking

the

endogenous

GSK-3

in

the

ventral

cells

of

the

early

embryo

leads

toformation

of

a

second

set

of

body

axisThe

role

of

Wnt

pathway

proteins

in

dorsal-ventral

axisspecification

(II)第16頁/共63頁Model

of

the

induction

of

the

Spemann

organizer

in

thedorsal

mesodermLocalization

of

stablized

beta-catenin

in

thedorsal

side

of

the

embryoActivation

of

Wnt

signaling

activates

genesencoding

proteins

such

as

SiamoisSiamois

and

TGF-beta

signaling

pathwayfunction

together

to

activate

the

goosecoid

genein

the

dorsal

portionGoosecoid

as

a

transcription

factor

activatesgenes

whose

proteins

are

responsible

forinduction

of

the

Spemann

organizer

in

the

dorsalmesoderm第17頁/共63頁How

was

the

organizer

specified

and

formed?

What

caused

the

dorsalblastopore

lip

to

differ

from

any

other

region

of

the

embryo?What

factors

were

being

secreted

from

the

organizer

to

create

thedorso-ventral

and

antero-posterior

axes?How

did

the

patterning

of

the

embryo

along

the

body

axes

becomeaccompanied?第18頁/共63頁Mechanisms

underlying

role

of

the

Spemann

organizer

indevelopment

of

the

body

planThe

functions

of

the

Spemann

organizer

(I)第19頁/共63頁The

ability

to

self-differentiate

dorsal

mesoderm

into

prechordal

plate,chordamesoderm(notochord脊索)etcThe

ability

to

dorsalize

the

surrounding

mesoderm

into

paraxial(somite-forming)

mesoderm

(When

it

would

otherwise

form

ventralmesoderm)The

ability

to

dorsalize

the

ectoderm,

inducing

the

formation

of

theneural

tubeThe

ability

to

initiate

the

movements

of

gastrulation.

Once

the

dorsalportion

of

the

embryo

is

established,

the

movement

of

the

involutingmesoderm

establishes

the

AP

axis.

In

Xenopus

(and

other

vertebrates),the

formation

of

the

AP

axis

follows

the

formation

of

the

DV

axisThe

functions

of

the

Spemann

organizer

(II)第20頁/共63頁The

Organizer

functions

in

setting

up

the

dorsal-ventral

axis

bysecreting

diffusible

proteins

(Noggin,

chordin,

and

follistatin)

that

antagonize/block

the

BMP

signal.

These

diffusible

proteins

generate

a

gradient

of

BMP

signaling

that

specifies

the

DV

axisThe

Organizer

is

able

to

secret

the

Wnt

blockers

Cerberus,

Dickkopfand

Frzb

in

the

anterior

portion

of

the

embryo

that

generate

a

gradient

of

Wnt

signaling.

Thus,

the

Wnt

signaling

gradient

specifies

the

AP

axis.第21頁/共63頁第22頁/共63頁第23頁/共63頁The

diffusible

signal

proteins

secreted

by

theSpemann

organizer

(I)第24頁/共63頁The

Organizer

functions

in

setting

up

the

dorsal-ventral

axisby

secreting

diffusible

proteins

(Noggin,

Chordin,

and

Follistatin)that

antagonize/block

the

BMP

signal.

These

diffusible

proteinsgenerate

a

gradient

of

BMP

signaling

that

specifies

the

DV

axisLocalization

of

noggin

mRNA

in

the

organizer

tissue第25頁/共63頁At

gastrulation,

noggin

is

expressed

in

thedorsal

blastopore

lipDuring

convergent

extension,

noggin

isexpressed

in

the

dorsal

mesoderm

(thenotochord,

prechordal

plate

etc

)Noggin

protein

is

important

for

development

of

the

dorsaland

anterior

structures

of

the

Xenopus

embryo第26頁/共63頁Rescue

of

dorsal

structures

by

Noggin

proteinMost

top:

The

embryo

lacks

dorsal

structures

due

toexposure

to

the

UVThe

2nd-4th

panel:

the

rescued

embryos

with

dorsalstructures

in

a

dosage-related

fasion,

when

the

defectembryo

is

injected

with

noggin

mRNAThe

bottom:

If

too

much

noggin

mRNA

is

injected,

theembryo

produces

dorsal

tissues

at

the

expense

ofventral

and

posterior

tissue,

becoming

little

more

than

ahead.Model

for

the

action

of

the

Organizer

in

specifying

the

DV

axis第27頁/共63頁P(yáng)-Smad1

antibody

staining

shows

thegradient

of

the

BMP

signaling

alongthe

DV

axis

in

an

early

gastrulatingXenopus

embryoA

gradient

of

BMP4

signalingelicits

the

expression

of

differentgenes

in

a

concentration-dependent

fasionThe

diffusible

signal

proteins

secreted

by

theSpemann

organizer

(II)第28頁/共63頁The

Organizer

is

able

to

secret

the

Wnt

blockers

Cerberus,Dickkopf

and

Frzb

in

the

anterior

portion

of

the

embryo

that

generatea

gradient

of

Wnt

signaling.

Thus,

the

Wnt

signaling

gradientspecifies

the

AP

axis.Cerberus,

a

secreted

protein

from

the

organizer

is

important第29頁/共63頁for

development

of

the

most

anterior

head

structuresInjection

of

Cerberus

mRNA

into

a

vegetal

ventral

Xenopus

blastomere

at

the

32-cell

stageinduce

ectopic

head

structuresFrzb,

another

secreted

protein

from

the

organizer

is

importa第30頁/共63頁for

development

of

the

most

anterior

head

structuresThe

frzb

is

expressed

in

the

headendomesoderm

of

the

organizerThe

frzb

mRNA:

dark

blueThe

chordin

mRNA:

brownMicroinjection

of

frzb

mRNA

into

themarginal

zone

leads

to

the

inhibition

oftrunk

formation,

due

to

inactivation

ofthe

Wnt

signalingThe

organizer

is

able

to

secret

different

sets

of

signal

prot第31頁/共63頁that

antagonize/block

BMP

and

(or)

Wnt

signaling第32頁/共63頁Mechanisms

underlying

role

of

the

Spemannorganizer

in

the

body

axis

formation第33頁/共63頁How

was

the

organizer

specified

and

formed?

What

caused

the

dorsalblastopore

lip

to

differ

from

any

other

region

of

the

embryo?What

factors

were

being

secreted

from

the

organizer

to

create

theantro-posterior

and

dorso-ventral

axes?How

did

the

patterning

of

the

embryo

along

the

body

axes

becomeaccompanied?第34頁/共63頁The

trunk

mesoderm

of

a

neurula-stage

embryo

can

be

subdividedinto

four

regions

along

the

dorso-ventral

axis第35頁/共63頁The

trunk

mesoderm

of

a

neurula-stage

embryo

can

be

subdividedinto

four

regions

along

the

dorso-ventral

axis第36頁/共63頁P(yáng)atterning

the

mesoderm

along

the

dorso-ventral

axis

(subdivisionof

the

mesoderm)

is

controlled

by

thegradient

of

BMP4

signaling.High

doses

of

BMP4

activate

those

genes

(e.g,

Xvent1)

for

development

of

the

lateral

plate

mesodermIntermediate

levels

of

BMP4

instruct

formation

of

the

intermediate

mesodermLow

doses

of

BMP4

regulate

the

paraxial

mesoderm

differentiation

through

activating

myf5

et

alThe

mesoderm

becomes

notochord

tissue

when

no

BMP4

activity

is

present

in

the

most

dorsal

regionThe

antero-posterior

axial

patterning

in

vertebratesPatterning

of

the

vertebrate

embryo

along

the

AP

axis第37頁/共63頁will

be

focused

on:Patterning

of

the

dorsal

mesoderm

that

forms

the

somites,

theblocks

of

mesodermal

cells

that

give

rise

to

the

skeleton

and

muscles

of

thetrunkPatterning

of

the

ectoderm

that

will

develop

into

the

nervoussystem.Patterning

the

body

plan

in

animals第38頁/共63頁Development

of

the

Drosophila

body

planSpecification

of

the

antero-posterior

and

dorso-ventral

axis

in

DrosophilaoocyteSetting

up

the

body

axes

in

DrosophilaPatterning

the

Drosophila

embryoPatterning

the

vertebrate

body

planSpecification

and

setting

up

of

the

body

axes

in

amphibians

(Xenopus)Somite

formation

and

antero-posterior

patterningPatterning

the

vertebrate

nervous

systemSpecifying

the

left-right

axis

(left-right

asymmetry

of

internal

organs)Neural

tube

and

somites

seen

by

scanning

electronmicroscopy第39頁/共63頁P(yáng)atterning

of

the

somite-forming

mesoderm

along

theantero-posterior

axisSomites

are

blocks

of

mesodermal

tissue

that

are

formed

aftergastrulation.

They

forms

sequentially

in

pairs

on

either

side

of

thenotochord,

starting

at

the

anterior

end

of

the

embryo

or

head

end.

Thesomites

give

rise

to

the

vertebrae,

to

the

muscles

of

the

trunk

andlimbs,

and

to

the

dermis

of

the

skin.Somites

differentiate

into

particular

axial

structures

depending

ontheir

position

along

the

AP

axis.The

anterior-most

somitesThose

posterior

to

themskullcervical

vertebraeMore

posterior

ones

thoracic

vertebrae

with

ribs第40頁/共63頁The

pre-somatic

mesoderm

is

patterned

along

its

AP

axis

beforesomite

formation

begins

during

gastrulation.The

positional

identity

of

the

somites

is

specified

by

thecombinatorial

expression

of

genes

of

the

Hox

complexs

along

the

AP

axis,

from

the

hindbrain

to

the

posterior

end,

with

the

order

ofexpression

of

these

genes

along

the

axis

corresponding

to

their

order

inthe

cluster

along

the

chromosomeMutations

or

overexpression

of

a

Hox

gene

results,in

general,in

localized

defects

in

the

region

in

which

the

gene

is

expressed,and

cause

homeotic

transformations（同源異型轉(zhuǎn)化）.第41頁/共63頁Somites

are

formed

in

a

well-defined

order

along

theantero-posterior

axisSpecification

of

the

pre-somitic

mesoderm

by

position

along第42頁/共63頁the

antero-posterior

axis

has

occurred

before

somiteformation

begins

during

gastrulationIdentity

of

somites

along

theantero-posterior

axis

isspecified

by

Hox

gene

expression

(I)第43頁/共63頁The

Hox

(Homeobox)

genes

of

vertebrates

encode

a

large

group

ofgene

regulatory

proteins

that

all

contain

a

similar

DNA-bindingregion

of

around

60

amino

acids

known

as

the

homeodomain.

Thehomeodomain

is

encoded

by

a

DNA

motif

of

around

180

base

pairs

termed

the

homeobox,

a

name

that

came

originally

from

the

fact

thatthis

gene

family

was

discovered

through

mutations

that

produce

ahomeotic

transformation—a

mutation

in

which

one

structure

replacesanother.

For

example,

the

four-winged

fly.Hox

genes

that

specify

positional

identity

along

the

AP

axis

wereoriginally

identified

in

Drosophila

and

it

turned

out

that

related

genesare

involved

in

patterning

the

vertebrate

axisIdentity

of

somites

along

theantero-posterior

axis

isspecified

by

Hox

gene

expression

(II)第44頁/共63頁All

the

Hox

genes

whose

functions

are

known

encode

transcriptionalfactors.

Most

vertebrates

have

four

separate

clusters

of

Hox

genes.A

particular

feature

of

the

Hox

gene

expression

in

both

insects

andvertebrates

is

that

the

genes

in

each

cluster

are

expressed

in

a

temporaland

spatial

order

that

reflects

their

order

on

the

chromosome.

That

is---a

spatial

pattern

of

genes

on

a

chromosome

corresponds

to

a

spatialexpression

pattern

in

the

embryo

(The

order

of

the

genes

in

each

cluster

from

3，to5，in

the

DNA

is

the

order

in

which

they

are

expressed

along

the

AP

axis).The

overall

pattern

suggests

that

the

combination

of

Hox

genes

provides

positional

identity

for

each

somite.

In

the

cervical

region,

forexample,

each

somite,

and

thus

each

vertebra,

could

be

specified

by

aunique

pattern

of

Hox

gene

expressionSpecification

of

the

identity(characteristic

strucutre)of

each

segmentaccomplished

by

the

homeotic

selector(同源異型選擇者)genes第45頁/共63頁lab

and

Dfd---the

head

segmentsScr

and

Antp---

the

thoracic

segmentsUbx

---

the

third

thoracic

segmentAbdA

and

AbdB---the

abdominal

segmentsHomeotic

gene

expression

inDrosophilaThere

are

2

clusters

of

thehomeotic

genes

encoding

theAntennapedia

and

bithoraxcomplexesLoss-of-function

mutations

in

the

Ultrabithorax

gene

can

transformthe

3rd

thoracic

segment

into

another

2nd

thoracic

segment,producing

a

four-winged

fly第46頁/共63頁第47頁/共63頁第48頁/共63頁Almost

every

region

in

the

mesoderm

along

the

antero-posterior

axisis

characterized

by

a

particularset

of

expressed

Hox

genes第49頁/共63頁第50頁/共63頁P(yáng)atterning

the

body

plan

in

animals第51頁/共63頁Development

of

the

Drosophila

body

planSpecification

of

the

antero-posterior

and

dorso-ventral

axis

in

DrosophilaoocyteSetting

up

the

body

axes

in

DrosophilaPatterning

the

Drosophila

embryoPatterning

the

vertebrate

body

planSpecification

and

setting

up

of

the

body

axes

in

amphibians

(Xenopus)Somite

formation

and

antero-posterior

patterningPatterning

the

vertebrate

nervous

systemSpecifying

the

left-right

axis

(left-right

asymmetry

of

internal

organs)The

ectoderm

lying

along

the

dorsal

midline

of

the

embryobecomes

specified

as

neuroectoderm,

the

neural

plate,during

gastrulationDuring

the

stage

of

neurulation,

the

neural

plate

formsthe

neural

tube,

which

eventually

differentiates

into

thecentral

nervous

system第52頁/共63頁第53頁/共63頁Rhombomere:菱腦節(jié)Branchial

arches:鰓弓第54頁/共63頁P(yáng)atterning

the

nervous

system

along

the

AP

axis第55頁/共63頁Hox

genes

are

expressed

in

the

mouse

embryo

hindbrain

in

a

well-defined

pattern,which

closely

correlates

with

the

segmental

pattern.Thus,Hox

gene

expression

may

provide

a

molecular

basis

for

theidentities

of

both

rhombomeres(菱腦節(jié))and

the

neural

crest

at

thedifferent

positions

in

the

hindbrain.Both

gene

mis-expression

or

gene

knock-outs

in

mice

have

alreadlyshown

that

change

in

the

Hox

gene

expression

causes

a

partial

orcomplete

homeotic

transformation

of

one

segment

into

another

in

thehindbrain.

Thus,

the

Hox

genes

determine

patterning

of

the

hindbrainregion

along

the

AP

axis第56頁/共63頁P(yáng)atterning

the

nervous

system

along

the

AP

axis第57頁/共63頁Hox

genes

are

involved

in

patterning

the

hindbrain,

but

Hox

geneexpression

can

not

be

detected

in

the

most

anterior

neural

tissues

ofthe

mouse—the

midbrain

and

forebrain.Instead,

homeodomain

transcriptional

factors

such

as

Otx

and

Emcare

expressed

anterior

to

the

hindbrain

and

specify

pattern

in

theanterior

brain

in

a

manner

similar

to

the

Hox

gene

more

posteriorly.

Inmice,

Otx1

and

Otx2

are

expressed

in

overlapping

domains

in

thedeveloping

forebrain

and

hindbrain,

and

mutations

in

Otx1

leads

tobrain

abnormalities

and

epileps