September 15, 2002;
Molecular regulation of vertebrate early endoderm development.
Detailed study of the ectoderm
has led to increasingly refined understanding of molecular mechanisms that operate early in development to generate cellular diversity. More recently, a number of powerful studies have begun to characterize the molecular determinants of the endoderm
, a germ layer previously neglected in developmental biology. Work in diverse model systems has converged on an integrated transcriptional and signaling pathway that serves to establish the vertebrate endoderm
. A T-box transcription factor identified in Xenopus embryos, VegT
, appears to function near the top of an endoderm
-specifying transcriptional hierarchy. VegT
activates and reinforces Nodal
signaling and also induces expression of essential downstream transcriptional regulators, Mix-like paired-homeodomain and GATA factors. These proteins cooperate to regulate expression of a relay of HMG-box Sox-family transcription factors culminating with Sox 17, which may be an obligate mediator of vertebrate endoderm
development. This review synthesizes findings in three vertebrate model organisms and discusses these genetic interactions in the context of the progressive acquisition of endodermal identity early in vertebrate development.
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FIG. 1. Anatomy of the early endoderm in Xenopus (A–C), zebrafish (D–F), and mouse (G, H) embryos, shown in conjuction with
schematic fate maps which depict the origin of the majority of the endoderm (A) in the vegetal hemisphere of Xenopus embryos and (D)
in the four marginal blastomere tiers in Danio (Warga and Nusslein-Volhard, 1999). (B) Photomicrograph of the Xenopus blastula (Hausen
and Riebesell, 1991), with pigmented ectodermal precursors in the blastocoel roof (top) and endoderm precursors in the vegetal pole
(bottom). Data are also shown for mRNA in situ hybridization for endodermal markers, Xsox17 (C) in Xenopus (Zorn et al., 1999b) and
Bonnie and clyde (Bon; side view in E, top view in F) in D. rerio (Kikuchi et al., 2000). (G,H) Mouse embryo at the end of gastrulation, when
the endoderm (arrows in G) is transiently an external tissue layer, and with the endoderm stripped away (H) to reveal its relationship to the
rest of the epiblast (Wells and Melton, 2000). Individual panels reprinted with permission from (B) Springer-Verlag Publishers, (D, G, and
H) The Company of Biologists Ltd., and (E and F) Cold Spring Harbor Laboratory Press.
FIG. 2. Transcription factors (green) and signaling proteins (blue, yellow) that function within recently elucidated pathways of early
endoderm differentiation in X. laevis (left) and D. rerio (right). Maternal (top) and zygotic (bottom) determinants are indicated, and the
progressive commitment of mesendodermal progenitors to endodermal cell fate is depicted as a continuum in the gray bar to the left. Solid
arrows indicate experimental evidence for induction or genetic interaction, whereas dotted arrows point to likely but yet unproven
relationships. To date, only a single Mix-like transcription factor, bonnie and clyde (bon), is implicated genetically in zebrafish endoderm
formation, in contrast to a panoply of related Mix proteins in Xenopus. Vg1 is a Xenopus TGF ligand not discussed in this review.
Orthologs for Xenopus Veg T and zebrafish casanova remain unidentified. The transcription factors shown probably function cell
autonomously; although the secreted proteins act on cells neighboring those that release them, autocrine action on producer cells
themselves is also likely.
FIG. 3. Schema of Nodal-related TGF signaling in Xenopus (left) and zebrafish (right) endoderm development. A variety of Nodal-related
ligands probably interact at the cell surface with a complex between selected Activin class IB-receptors and Cripto-related EGF-CFC
proteins (One-eyed pinhead in zebrafish, ? in Xenopus). These interactions activate latent transcriptional regulators, Smads, and FAST
proteins, that function in nuclear complexes to activate lineage-specific genes. One important challenge is to understand how the same
factors mediate a wide range of developmental effects, and one possibility, suggested for organizer genes (Germain et al., 2000) but yet
unproven in endoderm development, is depicted here. Besides established transcriptional mechanisms for responding to TGF signals (2),
Mix-like DNA-binding proteins, induced independently or in response to TGF signals, may act in conjunction with Smads (1) to activate
Nodal-responsive endoderm-specific genes. Zebrafish Bon is inferred by analogy to participate in gene regulation similar to the proposed
role of Xenopus Mix-like factors.