Transcript Signal Integration During Development Dan Weinstein Vertebrate development is characterized by a series of inductive interactions The three-signal model of mesoderm induction Germ-layer.

Signal Integration During Development
Dan Weinstein
Vertebrate development is characterized by a series of inductive interactions
The three-signal model of mesoderm induction
Germ-layer suppression/ “Head formation”
Xenopus laevis fate maps
Mesoderm formation: the 3 (or 4)-Signal Model
Ventral
Dorsal
1-make mesoderm
2-make dorsal mesoderm
3-pattern mesoderm
Very useful model, although “1” likely induces mesoderm throughout the equatorial zone,
and “2” and “1” act together on cells dorsally
Wolpert, Principles of Development (1998), Oxford Univ. Press
Signal 1: make mesoderm
Evidence for Signal 1: Nieuwkoop Recombinants
Figure from S. Sokol, MSSM
Signal 1=Smad2/3-mediated TGFb ligand; Ras/MAPK
signaling required for maintenance
FGF
Adapted from Kimelman and Griffin (1998), Cell 94, 419-421
mesoderm induction in Xenopus
VegT
Nodal-related ligand stimulates 2/3-type R-Smads
Adapted from: Massague (1998), Ann. Rev. Biochem. 67, 753-791;
Hama et al. (2001), Mech. Dev. 109, 195-204.
Signal 2: Make dorsal mesoderm
Wolpert, Principles of Development (1998), Oxford Univ. Press;
Gilbert, Developmental Biology, 7th ed.(2003), Sinauer Associates, Inc.
Evidence for Signal 2
Wolpert, Principles of Development (1998), Oxford Univ. Press
UV irradiation and the DAI
Wolpert, Principles of Development (1998), Oxford Univ. Press
Axial rescue
Slack (1994), Curr. Biol. 4, 116-126
Wolpert, Principles of Development (1998), Oxford Univ. Press
Figure 1. The Wnt canonical pathway
Alex Gregorieff et al. Genes Dev. 2005; 19: 877-890
The “canonical” Wnt pathway
http://www.stanford.edu/~rnusse/wntwindow.html
Dorsal stabilization/nuclear localization of b-catenin following cortical rotation
Gilbert, Developmental Biology, 7th ed.(2003), Sinauer Associates, Inc.;
Tao et al. (2005), Cell 120, 857-871.
Molecular integration of Signal 1 and Signal 2
Gilbert, Developmental Biology, 7th ed.(2003), Sinauer Associates, Inc.
Canonical and non-canonical Wnt pathways
Jessen and Solnica-Krezel (2005), Cell 120, 736-737.
Signal 3: Dorsalize Mesoderm/Antagonize Ventralizers of
Mesoderm
Evidence for a dorsalizing signal secreted by the Organizer
Along these same lines: dorsal recombinants
dorsalize ventral explants
Wolpert, Principles of Development (1998), Oxford Univ. Press
BMP4 signaling ventralizes mesoderm, and is inhibited dorsally
(dorsalization via inhibition of ventralization)
Phospho-Smad1 localization
Glinka et al. (1997) Nature 289, 517-519;
Gilbert, Developmental Biology, 7th ed.(2003), Sinauer Associates, Inc.
Mechanism of action of the dorsalizing, neuralizing, BMP antagonists
Chordin, Noggin, and Follistatin
Noggin expression
Wolpert, Principles of Development (1998), Oxford Univ. Press
BMPs and their antagonists represent Signals 3 and 4;
these factors pattern all three germ layers during gastrulation
Munoz-Sanjuan and Brivanlou (2002), Nat. Rev. Neurosci. 3, 2721-280.
Gilbert, Developmental Biology, 7th ed.(2003), Sinauer Associates, Inc.
Weinstein and Hemmati-Brivanlou (1997), Curr. Opin. Neurobiol. 7, 7-12.
Ectopic germ layer suppression:
Xbrachyury promoter analysis
x
Xbr a chyur y
Xbr a chyur y
x
Xbr a chyur y
Modeled after: Lerchner et al. (2000), Development 127, 2729-2739.
Ectopic germ layer suppression:
“rogue cells”
Early gastrula
Modeled after: Wardle and Smith (2004), Development 131, 4687-4696.
Late gastrula
Mesendodermal suppression by zygotic Fox proteins
Suri et al (2005), Development 132, 2733 - 2742
Mesodermal suppression by the maternal Smad4 ubiquitin ligase Ectodermin
Dupont et al. (2005), Cell 121, 87-99.
Gastrulation in the mouse
Anterior fate requires suppression of posterior (mesodermal) fate
Removal of chick hypoblast (and thus Nodal-antagonist activity),
or targeted deletion of Cerl and Lefty1 in the mouse AVE gives rise to
multiple primitive streaks (ectopic mesoderm).
Figures adapted from:
Weinstein, D.C. (2004). In Stern, C. (ed.), Gastrulation, Cold Spring Harbor Laboratory Press, 563-570;
Perea-Gomez et al. (2002), Dev. Cell 3, 745-756.
“Head Induction”
Dual inhibition of BMP and (zygotic) Wnt signaling leads to
formation of a complete secondary axis
Glinka et al. (1997) Nature 389, 517-519.
Cerberus makes extra heads only (no extra trunk)-Anti-Wnt? + Anti-BMP? + Anti-trunk inducer? Yes.
Bouwmeester et al. (1996), Nature 382, 595-601;
Piccolo et al. (1999), Nature 397, 707-710
Formation and patterning of the primary germ layers
Signal 1/mesendoderm induction--Smad 2/3 + Ras/MAPK
Signal 2/dorsal axis formation--Canonical Wnt pathway,
activated maternally
Signal 3/DV patterning (all germ layers)--Smad 1/5 activation/suppression
Ectodermal development--inhibit Smad 1/5, inhibit Smad 2/3,
inhibit zygotic canonical Wnt signaling