Cell movements during gastrulation suggest geometry for the embryo

Frog

Chick

A

P

A

P

Frog

Chordin Chordin ChordinDorsal lip of Dorsal lip of

blastoporeblastopore

Chick

Gene expression, particularly in mesoderm, and local signaling distinguishA-P axis from early gastrulation onward in register with cell movements

…and antagonistic signaling establishes further local and axial distinctions

The geometry of cell movements during gastrulation in the mouse isdistinct, but the results are the same…

head

tail

Noggin

signal

antagonist

TF target

TF target

Germ layers are divided into anterior (head) and posterior (tail)territories by antagonistic signaling pathways that result in

local expression of transcription factor targets

Essential antagonist/agonist pairs of signals, from distinct localsources establish A-P patterning in the germ layers

Anteriorizing Posteriorizing

nogginchordin

DkkSFRPs

LeftyCerberus

The localization of antagonists in the anterior region suggeststhat “head” is a default, and “tail” must be actively constructed

Bmps

Wnts

Nodal

A schematic review of Bmp Signaling

+/+ Chord-/- Nog:Chord-/-

Loss of Bmp antagonist function disrupts head development

Multiple mechanisms can inhibit Wnt Signaling

Loss of Wnt antagonism via Dkk causes head to be transformed into posterior tissue

Nodal signaling uses pathways similar to that for Bmp:both are members of the Tgf superfamily of signals

Loss of Nodal antagonism causes expansion of visceral endoderm,normally restricted to posterior of embryo

Hex is a marker for visceral endoderm

Heads or Tails: The balance of Bmp, Wnt and Nodal signalingdecides!

Paralogues on different chromsomes:3’=anterior, 5’=posterior

There is more to posterior development than making a tail:posterior regionalization via the Hox genes

Colinear expression relies on temporally controlled chromatin remodeling in a 3’to 5’ direction

Is there a terminal posterior identity: ParaHox genes andestablishing the end of the “tail”

most posteriorly restrictedin all 3 germ layers

Head/Tail antagonismholds for RA signaling

Regulation of Hox/ParaHox expression reflects antagonist/agonist signaling

Raldh2RA synthesizingenzyme

Cyp26RA degradingenzyme

Ho

xb1

RA

Cyps

Posterior signals include Wnts, and Fgfs:establish graded gene expression in concert with RA

Hox in the head: maintaining posterior segmentation inanteriorized territory

ParaHox and Hox genes are central regulators of A-P identity

1.Conditional mutation ofCdx2 in the post-gastrulaendoderm causes posteriorgut dismorphogenesis

2a.Primary differentiated cellular characteristics of intestinal epithelium areabsent in posterior gut ofCdx2 conditional mutant

goblet cells (alcian blue)

enterocytes:alkalinephosphatase

2b. Cellular architecture is disrupted, and cell proliferation is altered in posterior gut ofCdx2 conditional mutant

3. The dysmorphogenic posterior gut has been “anteriorized” to resemble esophageal epithleium by loss of Cdx2 in post-gastrulaendoderm.

4. Anteriorization ofgut epithelium toesophageal epitheliumis accompanied byshifted expression(spatial or temporal)of anterior endodermgenes, including Hox cluster

5. Shift of expression of Wnts, transcriptional regulators,and down stream targets (all evidence of M-E signaling in which Wnt10a, 3a are available from M and act on E) in anterior gut, and in posterior mutant gut