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Developmental Biology – Biology 4361. Axis Formation and Mesoderm Induction. October 27, 2005. - polarized eggs – animal/vegetal. - pigment. - yolk v. clear cytoplasm. - mitochondrial cloud. - germinal vesicle. - localized cytoplasmic components. Amphibian anteroposterior specification.

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Developmental Biology – Biology 4361

Axis Formation and

Mesoderm Induction

October 27, 2005

amphibian anteroposterior specification

- polarized eggs – animal/vegetal

- pigment

- yolk v. clear cytoplasm

- mitochondrial cloud

- germinal vesicle

- localized cytoplasmic components

Amphibian anteroposterior specification
anteroposterior axis vegt depletion1
Anteroposterior axis – VegT depletion

normal

VegT - depleted

depletion of VegT =

- shift from endoderm to mesoderm and ectoderm

- mesoderm replaced with ectoderm

- animal region forms only epidermis and no nervous system

Figure 9.7

dorsalization xenopus
Dorsalization - Xenopus

UV = ventralized

Figure 9.18

cortical rotation and disheveled

sperm

Disheveled

protein (Dsh)

Dsh

Cortical rotation and Disheveled

1. Fertilization

2. Cortical rotation

3. Dorsal enrichment

of Dsh

disheveled activity
Disheveled activity

gylcogen synthase

kinase-3

Figure 9.21

disheveled activity1

Disheveled protein

blocks GSK-3 phosphorylation of b-catenin

Disheveled activity

gylcogen synthase

kinase-3

Transcription factor

Figure 9.21

molecular basis of dorsoventral axis

Repressed

Molecular basis of dorsoventral axis

b-catenin stabilized

b-catenin degraded

b-catenin

proteins

Tcf-3

proteins

siamois

gene

siamois

gene

Siamois

protein

Activated

TGF-b

signaling

pathway

transcription

goosecoid

gene

Goosecoid

protein

transcription

organizer transplant
Organizer transplant

Spemann’s organizer – dorsal lip of the blastopore

organizer proteins
“Organizer” proteins

- expressed almost exclusively in the organizer

Nuclear Proteins

Secreted Proteins

chordin

XLim1

Xnot

noggin

nodal-related proteins

Otx2

(several)

XFD1

Cerberus

XANF1

Goosecoid

Follistatin

Frzb

Gilbert: Developmental Biology, 7th ed (2003) Table 10.2.

organizer gene activity
Organizer gene activity

goosecoid mRNA can induce a second dorsal axis:

goosecoid mRNA injection causes formation of a second dorsal blastopore lip

produces embryo with two dorsal axes and two sets of head structures

Gilbert: Developmental Biology, 7th ed (2003) Fig 10.28.

organizer gene activity1
Organizer gene activity

Rescue of dorsal structures by noggin protein:

ventralized embryo without dorsal structures

(UV-irradiated)

dose-dependent induction of dorsal

structures by injection of noggin mRNA

“overdose” of noggin mRNA causes formation

of dorsal structures at the expense of

ventral structures

noggin binds to bone morphogenic proteins

(BMP2 & BMP4)

- inhibits binding BMP receptor binding

Gilbert: Developmental Biology, 7th ed (2003) Fig 10.30.

organizer gene activity2
Organizer gene activity

chordin mRNA is localized in the ‘organizer’:

- chordin mRNA is found in the dorsal lip

- late in gastrulation, chordin is localized in the dorsal mesoderm of the notochord

- chordin protein binds to BMP4 and BMP2 – inhibits receptor BMP-receptor binding

- inhibition of BMP4 & BMP2 induces formation of the neural tube

in adjacent ectoderm

Gilbert: Developmental Biology, 7th ed (2003) Fig 10.32.

mesoderm induction xenopus3
Mesoderm induction - Xenopus

mesoderm inducers:

Vg1

bFGF

activin

Figure 9.9a, b

mesoderm induction organizer formation
Mesoderm induction, Organizer formation

Nodal

related

high

BMP4

low

β-catenin

Organizer

VegT, Vg1

Nodal

related

low

BMP4

high

Ventral

mesoderm

1. β-catenin acts with VegT and Vg1 to activate Xnr genes (Xenopus Nodal-related)

2. Organizer originates in the region where VegT & Vg1 and β-catenin overlap

3. Gradient of Xnr protein specifies mesoderm: low Xnr  ventral mesoderm

4. High Xnr levels activate goosecoid and other ‘organizer’ genes

left right asymmetry
Left-right asymmetry

Most animals are bilaterally symmetrical (Bilateria)

- however, individuals deviate to some degree from true bilateral symmetry:

- fluctuating asymmetry: non-heritable minor left-right differences

- antisymmetry: heritable morphological left-right differences

- sidedness is randomly distributed (ca. 50% each)

  • - regular asymmetry or directed asymmetry:
  • sidedness is fixed for a species or for a higher taxon
          • e.g. in humans:
          • - heart on left side
          • - stomach curves to the left
          • - liver & spleen on right side
left right asymmetry1
Left-right asymmetry

Deviation from directed asymmetry is often lethal!

- situs inversus: complete reversal of left-right symmetry in all organs

- heterotaxis: some organs reversed

- isomerism: normally asymmetrical organs duplicated or missing

left right asymmetry2
Left-Right Asymmetry

Mechanistic basis for establishing asymmetry:

- chiral molecules may cause “symmetry-breaking” event

(specific orientation of stereoisomeric molecules relative to the body axes)

- translated into left-right differences at the level of cells, tissues

and the whole organism

Candidate chiral molecule: Dynein

- motor protein complex associated with axonemes, cilia

left right asymmetry3
Left-Right Asymmetry

Dyneins - microtubule-associated motor protein complexes

Fig 2.7.

Axonemal dyneins:

- chiral: curve clockwise (from base) = ‘handedness’

- mediate sliding between adjacent microtubules in cilia or flagella

- cause cilia to rotate in a specific direction (clockwise)

- monocilia (at Hensen’s node - mouse) generate oriented flow of signal molecules

to the left side of the embryo

- signal molecules activate or inhibit patterning genes on left side

iv and inv

iv+: ‘situs inversus viscerum’

- iv protein is a left-right dynein

- iv-/iv- = no motility, no fluid flow

- randomized L-R asymmetry (lethal)

inv+: “inversion of embryonic turning”

- wild type & heterozygous embryos turn clockwise

- inv-/inv- turn counterclockwise in amniotic cavity

- 100 % of homozygotes for inv show situs inversus

- mechanism of inv action is unknown

Iv+ and Inv+
nodal activated by iv inv

wild type

ectopic

Nodal activated by iv,inv

Nodal

- intracellular protein - TGF-β family

- nodal gene activated by iv and inv genes

- nodalprotein synthesized in left lateral plate mesoderm

- mesoderm adjacent to nodal expression develops into asymmetrical organs

  • ectopic expression of nodal on right side randomizes location of the heart

- nodal is involved in determining left-right asymmetry in mice, frogs,

chicken & zebrafish

nodal expression in mouse:

pitx2 lefty activated by iv ivn nodal
Pitx2 & lefty activated by iv, ivn, nodal

pitx2+ and lefty+ genes :

- pitx2 expressiondepends on iv,ivn and nodal genes

- pitx2 and lefty encode homeoboxtranscription factors that regulate genes

- both are expressed primarily on left side of vertebrate embryos

have been found in all vertebrates studied

- injection of ptx2 on right side of embryo

- can cause a complete reversal

of gut coiling and heart looping

nodal,pitx2 and leftyform an evolutionary

conserved signaling system that is

involved in regulating left-right

asymmetry in all vertebrates

pitx2 injection in Xenopus: