Is Chordin a morphogen?
Joanne Hama and Daniel C. Weinstein*
Summary
Models employing gradients of diffusible morphogens
are often invoked to explain regional specification in the
early embryo. In these models, a concentration gradient
of a secreted factor generates distinct cell fates, based on
the differential response of cells to local concentrations
of this morphogen. In recent years, there has been a great
deal of focus on the factors involved in the dorsoventral
patterning of the vertebrate mesoderm and ectoderm.
Dorsoventral specification during amphibian gastrula-
tion is regulated by the antagonistic actions of the Bone
Morphogenetic Proteins (BMPs) and a number of dorsally
expressed inhibitors, including the secreted factor,
Chordin. In a recent paper,
(1)
Blitz and colleagues explore
the possibility that Chordin acts as a long-range factor in
the amphibian gastrula embryo, to establish a functional
gradient of BMP activity. BioEssays 23:121±124, 2001.
ß 2001 John Wiley & Sons, Inc.
Introduction
In the frog Xenopus laevis, the specification of the dorsoventral
axis occurs via the formation of Spemann's organizer, a dorsal
mesendodermal signaling center. Although it has long been
recognized that the organizer is the source of signals responsi-
ble for the dorsalization of both gastrula-stage mesoderm and
ectoderm, the molecular nature of these signals has only come
to light within the past decade. It is now clear that the organizer
is the source of secreted antagonists that function only to
inhibit receptor-mediated induction of ventral fates by widely
expressed ligands.
(2)
The ventral inducing signals include
Bone Morphogenetic Proteins (BMP) 2, 4, and 7, members of
the Transforming Growth Factor b (TGFb) ligand superfamily.
All three factors are widely expressed in the gastrula ectoderm
and mesoderm, although BMP4 is excluded from the organizer
and a region of the dorsal ectoderm.
(3)
Chordin, Follistatin,
Noggin, Xnr3, and Cerberus, five structurally unrelated,
secreted factors expressed in Spemann's organizer, all
appear to function as inhibitors of BMP pathway activation.
(2)
The combination of a widely expressed ventralizing signal
and an antagonist expressed only in the organizer is sufficient
to establish two distinct zones of activity. On the ventral side of
the embryo, high levels of BMP and an absence of antagonist
lead to the establishment of ventral fates; these include blood
and epidermis in the mesoderm and ectoderm, respectively.
Conversely, on the dorsal side of the embryo, high levels of
BMP antagonists block BMP receptor activation, resulting in
the generation, by ``default,'' of dorsal fates; the somites and
neural tissue are examples of dorsal mesodermal and ecto-
dermal cell types.
(4)
A more complicated issue arises when
one attempts to envision what occurs between these two
poles. Embryologically, it is clear that there are intermediate
fates derived from the so-called lateral marginal zone of
mesoderm (including the precursor of the kidney), as well as
on the border between the regions fated to become epidermis
and neural tissue in the animal pole ectoderm (for example, the
cells of the neural crest). The establishment of such inter-
mediate fates could be explained if the BMP antagonists act
over a long range, with the effect of establishing a concentra-
tion gradient of BMP activity within the gastrula embryo (Fig. 1).
Cells located at different positions within this gradient would be
expected to respond differentially to the local concentration of
BMP, leading ultimately to distinct cellular fates. In such a
model, the organizer proteins could be said to function as
morphogens; that is, these factors influence cell fates at a
distance from their source, and elicit distinct cellular responses
at distinct concentrations.
(5)
This scenario differs slightly from
more classical morphogen models, in that the concentration
gradient that is established is of BMP activity, rather than that
of the long-range antagonists themselves. Such morphogen
models are widely invoked by developmental biologists, but
their role during vertebrate embryogenesis has been difficult to
prove. In a recent article,
(1)
Blitz and colleagues use a variety
of assays to address whether the organizer protein Chordin
acts as a long-range factor to establish a BMP gradient in the
gastrula marginal zone.
Chordin can act at a distance
Chordin is a secreted, 120 kDa protein that binds to BMP
homodimers and heterodimers with high affinity; binding of
Chordin prevents BMP from interacting with and activating its
receptors.
(6,7)
If Chordin acts as a long-range mediator of BMP
activity, it should, first and foremost, be able to act at a
distance. To examine the range of Chordin activity, Blitz et al.
first examined its ability to block the expression of Xvent2,a
BioEssays 23:121±124, ß 2001 John Wiley & Sons, Inc. BioEssays 23.2 121
Department of Pharmacology, Mount Sinai School of Medicine, New
York, New York.
Funding agencies: The Speaker's Fund for Biomedical Research:
Toward the Science of Patient Care, awarded by the City of New York,
and the AMDeC Foundation of New York City, through its ``Tartikoff/
Perelman/EIF Fund for Young Investigators in Women's Cancers.''
Correspondence to: Daniel Weinstein, Department of Pharmacology,
Mount Sinai School of Medicine, New York, NY 10029-6574. E-mail:
weinsd01@doc.mssm.edu
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