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Animal models of ventral body wall closure defects A personal perspective on gastroschisis.

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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 148C:186– 191 (2008)
A R T I C L E
Animal Models of Ventral Body Wall Closure
Defects: A Personal Perspective on Gastroschisis
TREVOR WILLIAMS*
Malformations affecting the ventral body wall comprise one of the leading categories of human birth defects.
Gastroschisis is a particularly important body wall closure defect as its incidence is rising worldwide. Although the
occurrence of such defects is relatively common their molecular and cellular basis is very poorly understood. A
robust animal model system to study the etiology of gastroschisis would be very useful, but several problems
currently hamper the identification of such a model. A concerted effort is required to recognize, characterize, and
classify ventral body wall defects in animal model species so that progress can be made in determining the
mechanisms of ventral body wall closure during human development as well as combating the increased
incidence of gastroschisis worldwide. ß 2008 Wiley-Liss, Inc.
KEY WORDS: gastroschisis; omphalocele; umbilical hernia; ventral body wall; animal models
How to cite this article: Williams T. 2008. Animal models of ventral body wall closure defects: A personal
perspective on gastroschisis. Am J Med Genet Part C Semin Med Genet 148C:186–191.
INTRODUCTION
Ventral body wall closure abnormalities
are common human birth defects
present in about one out of every 2000
live births [Chabra and Gleason, 2005;
Feldkamp et al., 2007]. Aberrant formation and closure of the ventral body
wall in humans can result in several
pathologies with distinct appearances
and these can be understood and classified with respect to the involvement of
the umbilical cord and associated umbilical ring [Brewer and Williams, 2004a;
Chabra and Gleason, 2005; Feldkamp
Trevor Williams is the Timpte/Brownlie
Chair in Craniofacial/Molecular Biology and
an Associate Professor at the University of
Colorado Denver Anschutz Medical Campus.
He received his undergraduate and graduate
training in Pathology and Molecular Biology
in England before moving to U.C. Berkeley
for post-doctoral studies. His research interest include the transcription factors and
signaling molecules regulating vertebrate
embryonic development with particular
focus on birth defects of the face, eye, limb,
and body wall.
*Correspondence to: Trevor Williams,
Department of Craniofacial Biology, Mailstop
8120, P.O. Box 6511, Aurora, CO 80045.
E-mail: trevor.williams@uchsc.edu
DOI 10.1002/ajmg.c.30179
ß 2008 Wiley-Liss, Inc.
et al., 2007; Vauthay et al., 2007]. Such
defects include umbilical cord hernia,
omphalocele, and gastroschisis (see
Figs. 1 and 2) of which the latter two
have the greatest clinical impact for
newborns and are the costliest to treat
(http://www.marchofdimes.com/aboutus/
680_2173.asp). There are now several
animal models for omphalocele including the Tcfap2a (AP-2a) knockout mouse and a chick model using
cadmium as a teratogen [Brewer and
Williams, 2004b; Thompson and Bannigan, 2007]. However, animal models
with gastroschisis are rare, and a definitive model of an isolated human gastroschisis is currently lacking. The absence
of a suitable model system adversely
impacts our understanding of the human
animal models with
gastroschisis are rare, and a
definitive model of an isolated
human gastroschisis is currently
lacking. The absence of a
suitable model system adversely
impacts our understanding of
the human pathology
pathology. Below, I discuss issues of
terminology that have complicated the
characterization of gastroschisis in animals as well as suggestions to identify
such models.
An umbilical cord hernia occurs when
the ventral body wall has closed normally about the umbilical cord, but a
portion of the gut occupies the base of
the cord along with the normal blood
vessels. This pathology may be caused by
incomplete retraction of the midgut into
the body cavity during earlier stages of
development. In omphalocele the umbilical ring, which is the transition zone
between the ectoderm and mesoderm
of the body wall and the amnion, is
abnormal and enlarged. During normal
development the umbilical ring closes so
that it is the same size as the circumference of the umbilical cord by the end
of the fetal period. A mature body wall
covers the ventral surface surrounding
the ring and the cord. With omphalocele, the umbilical ring is much larger
than the insertion point of the cord and
the mature body wall is limited to the
peripherary of the defect. Typically, the
umbilical cord will be in its normal
position at the centre of this defect, but
unlike an umbilical hernia, the gut
contents are not present in the cord.
Instead, the visceral contents including
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
187
Figure 1. Graphical representation of the normal appearance of the ventral body wall in a newborn mouse along with the three body
wall closure defects discussed in this review. Each panel shows a whole mount ventral view of the mouse torso (left) and a transverse section
through the region of the umbilical cord (right). A, amnion; D, dorsal; G, gut; L, liver; T, tail; UC, umbilical cord; VBW, ventral body wall.
the liver and gut can protrude through
the enlarged ring into the amniotic
sac. The extent of the omphalocele
is variable and the effected area may
occupy just the immediate vicinity of the
cord, or it may be far more extensive and
include both the abdomen and the
thorax. In gastroschisis, the body wall
closure defect and the cord are often
juxtaposed, but can also be separated by a
strip of mature body wall. Thus, as
opposed to an umbilical cord hernia or
an omphalocele, the cord is not necessarily part of the affected region of
Figure 2. Lateral views of E18.5 mice with a normal ventral body wall (A), an
omphalocele (B), or an apparent gastroschisis (C). UC, umbilical cord. The mouse in
Panel C presented as a rare isolated event in a litter in the laboratory of the author.
the ventral body wall in a gastroschisis.
The defect is normally to the right of the
umbilicus and presents with loops of
bowel extending out of the fissure in the
body wall with no amniotic covering.
Note that in an omphalocele the visceral
contents can also sometimes rupture
I would therefore suggest the
following system to identify a
gastroschisis in any vertebrate
species: loops of bowel
extending through body wall
with no amnionic covering;
a normal umbilical cord (both
in length and morphology); an
umbilical ring that is not
unusually large.
188
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
through the amnion, so this aspect of
the pathology is not a distinguishing
feature of a gastroschisis. I would therefore suggest the following system to
identify a gastroschisis in any vertebrate
species: loops of bowel extending
through body wall with no amnionic
covering; a normal umbilical cord (both
in length and morphology); an umbilical
ring that is not unusually large. Unresolved questions with regards to human
gastroschisis include its developmental
origins, the mechanism responsible for
the right side laterality bias, the overall
incidence of skin bridges in the condition, and if the presence or absence of
skin bridges provide clues to the etiology
of this birth defect. Unfortunately, to
date, studies in other animal species have
been unable to provide insight into these
issues.
The classification of human ventral
body wall closure defects listed above
was essentially adopted in the 1950s
[Chabra and Gleason, 2005; Chabra,
2007]. Before that point, all ventral body
wall closure defects were generally
referred to as a ‘‘gastroschisis’’. However,
the switch in terminology with respect
to gastroschisis in the human condition—where it now has a much more
specific meaning—does not appear to
have been widely applied in veterinary
pathology [Szabo, 1989]. This has meant
a degree of confusion when ventral body
wall defects in other mammalian species
are compared with the human condition. Specifically, references to gastroschisis in studies on mouse, rats, or farm
animals can cover any type of ventral
body wall closure defect and not just
a human ‘‘gastroschisis.’’ In many such
reports the term gastroschisis is often
used only in a table of observed defects
with no definition or illustrations of the
actual body wall phenotype. Therefore,
without an overt description, illustration, or photodocumentation of the
pathology, great care should be taken in
extending findings on ‘‘gastroschisis’’ in
animal models to the precisely defined
human condition. One clear recommendation for the future is that nomenclature for body wall closure defects be
consistent between human and other
animal species.
VENTRAL WALL BODY
DEFECTS
The nomenclature aside, there are
several other problems facing scientists
and veterinarians confronted with a
ventral body wall closure defect. Foremost is that the process of normal ventral
body wall closure is very poorly understood in comparison to many other
developmental processes [Brewer and
Williams, 2004a]. Thus, compared with
for example limb, brain, eye, or pancreas
development, there is no clear morphogenetic framework that can be used as a
guide to interpret one’s findings [Kaufman, 1992; Kaufman and Bard, 1999;
Rossant and Tam, 2002]. In vertebrates,
there is no consensus regarding the
tissues required, the cell shape changes
that might drive the process, or the
biological mechanisms responsible for
movement and fusion of the body wall
components. Similarly, few genes have
been identified that regulate this process,
and their expression patterns in the tissue
layers purported to govern ventral body
wall closure are almost completely
unknown at present [Brewer and Williams, 2004a]. This is of considerable
concern because it will tend to result
in body wall closure defects receiving
little attention in the many new mouse
models being characterized compared
with associated pathologies in developmental systems that are better understood.
The study of body wall closure
defects, particularly gastroschisis, in
non-human mammals is also prone to
some technical problems. If the offspring
are studied after birth, it is likely that
their mothers will cannibalize those
newborns possessing body wall closure
defects soon after parturition. Thus,
animals will need to be observed and
characterized during embryogenesis
and/or immediately after parturition.
Although this is an important consideration, it has not necessarily hampered
studies on other pathologies such as
neural tube closure defects. But another
problem facing those wishing to find
animal models for gastroschisis is the
common method used for the isolation of
embryos—particularly mouse embryos
ARTICLE
that constitute by far the largest experimental sample. In mice, a ventral body
wall defect will not be readily apparent
until after embryonic day 14.5. At these
later stages of development, the common procedure to isolate the embryos
would be to obtain an intact yolk sac.
The yolk sac would then be breached
and the embryo separated from the
attached placenta by pulling on the
intervening umbilical cord. This methodology almost inevitably leads to
damage at the attachment site of the
umbilicus to the abdominal wall. If a
gastroschisis is present, it is unlikely that
the thin strip of mature skin between
the umbilicus and the body wall defect
would remain intact. This would therefore tend to obscure the difference
between the various types of possible
body wall closure defects in any initial
analysis. So, a further recommendation
from this review is that embryos with
a clear body wall closure defect are
processed and characterized with the
umbilical attachment to the placenta still
intact.
Notwithstanding the issues noted
above, it would be very valuable to have a
robust animal model of gastroschisis that
could be used to probe the etiology of
the pathology and to test specific treatments for efficacy at suppressing this
birth defect, for example, maternal
dietary supplements. Ventral body wall
closure defects have been documented
to occur occasionally in offspring from
many vertebrate species including mice,
rats, guinea pigs, rabbits, dogs, cats,
horses, cattle, sheep, and pigs [Szabo,
it would be very valuable to
have a robust animal model of
gastroschisis that could be used
to probe the etiology of the
pathology and to test specific
treatments for efficacy at
suppressing this birth defect,
for example, maternal
dietary supplements.
ARTICLE
1989]. The incidence is often quite low,
<1%, although in some studies of kittens
and piglets the frequency of the defect
has approached 5%. As noted above, it is
often not possible to determine whether
many of these defects are equivalent
to the modern definition of a human
gastroschisis or represent other types of
body wall defect due to the lack of
documentation. Previous analyses also
failed to produce convincing data for a
genetic basis for gastroschisis in these
animal species. Nevertheless, it is worth
noting that several studies on cats, mice,
and rabbits indicate that ventral body
wall closure defects are more prevalent
in certain breeds, indicating a potential
genetic component [Collins et al., 2006;
Hillebrandt et al., 2003; Szabo, 1989].
Similarly, certain pig, rat, dog, cattle and
horse breeds may have a predisposition
to umbilical hernias [Szabo, 1989].
However, the low incidence of such
ventral body wall closure defects in most
of these animal species means that they
do not currently provide a robust model
system to follow the development and
genetic linkage of this pathology. One
exception is the inbred HLG/Ze mouse
strain, in which it has been possible to
map several loci that are responsible for
an increase in ventral body wall closure
defects following radiation exposure
[Hillebrandt et al., 1998, 2003]. Also of
interest is a large-scale genetic analysis of
various traits in different dog breeds that
could potentially be used to determine
genetic linkage in breeds prone to
this pathology [Szabo, 1989; Pennisi,
2007].
ANIMAL MODELS
Clear evidence that gene mutations can
cause ventral body wall closure defects
has been obtained by forward and
reverse genetic approaches in the mouse
[Hubner et al., 2001; Spiegelstein et al.,
2004; Brewer and Williams, 2004a;
Ogi et al., 2005; Shimizu et al., 2005;
Thumkeo et al., 2005; Goldman
et al., 2006; Hart et al., 2006; Hirano
et al., 2006; Wojcik et al., 2006;
Sun et al., 2007]. Here, a growing list
of genes and chromosomal loci are associated with body wall closure defects,
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
but again exactly how many of these
mutants model human gastroschisis will
require further study. For this reason,
it would be very useful if there were
a dedicated central repository with a
trained pathologist to study and classify
new mouse models. Such a center could
be modeled on those available through
The Jackson Laboratory, for example,
the ‘‘Craniofacial Mutant Resource’’
(http://www.jax.org/cranio/index.html).
Experimental models of gastroschisis
and omphalocele can also be generated
in chick, rodents, rabbits, and cats with
various teratogens, by irradiation, or via
other insults [Szabo, 1989; Baatout et al.,
2002; Hillebrandt et al., 2003; Brewer
and Williams, 2004a; Yan and Hales,
2006; Feldkamp et al., 2007; Thompson
and Bannigan, 2007]. But here again it is
often unclear if reports of gastroschisis
are comparable with the modern human
definition. Other issues in teratogenesis
studies are a low frequency of the
pathology and inconsistent phenotype in
the extent of the body wall closure
defect. Multiple overlapping anomalies
in other developmental systems can also
be problematic. Of note, a mouse model
combining low dietary protein and
zinc with excess exposure to carbon
monoxide produced a high incidence
(50%) of ventral body wall closure
defects [Singh, 2003]. Several of the
affected embryos had the hallmark of
gastroschisis—loops of bowel extruding
through a hole in the body wall separate
from the umbilicus [J. Singh, personal
communication]—although this was
not documented photographically. These
mice also had multiple additional developmental defects and so do not serve
as a definitive model of human gastroschisis, which usually occurs as an
isolated defect. Nevertheless, this teratogenic model may still serve as one of
the best paradigms to study the development of gastroschisis during mammalian
embryogenesis. Ideally, though, it would
be valuable to identify a genetic model
that produced a fully penetrant and
consistent gastroschisis phenotype that
could be followed throughout embryogenesis.
Finally, given the prevalence of the
mouse as both a genetic and teratogenic
189
model system to study ventral body wall
closure defects it is pertinent to ask
whether it represents the best possible
system to model this process in human
development. One concern is simply the
difference in size between the newborn
mouse and human. Thus, it might be
imagined that the ability to form or
sustain a small strip of skin between the
umbilicus and a gastroschisis defect
would be more difficult in the mouse
than in the larger human. Under such
circumstances, if the skin bridge broke
the gastroschisis would ‘‘migrate’’ to the
umbilicus and appear on first examination more like a small omphalocele that
had subsequently ruptured through the
amnion. A second problem concerns
the different morphogenetic programs
that occur during mouse and human
development around gastrulation and
shortly thereafter. At the end of gastrulation, around E8.0, the mouse embryo
is a U-shaped structure with the primitive gut located on the outer convex
surface, facing the antimesometrial pole
of the implantation site. The yolk sac
is attached at the anterior end of the
foregut and the posterior end of the
hindgut and loops back to surround
the entire embryo before integrating
with the ectoplacental cone at the
mesometrial pole. Thus, the yolk sac
cavity is in direct contact with the gut
and also surrounds the entire embryo
up until the ectoplacental cone. The
mouse embryo undergoes a process of
‘‘turning’’ between E8.5-9.5 resulting
in an inversion of the germ layers. This
process establishes the final relative
positions of the tissue layers associated
with the ventral body wall [Brewer and
Williams, 2004a]. Any defect in turning
will therefore have a profound effect on
mouse body wall formation. After turning, the association of the yolk sac with
the embryo proper in the midgut region
is lost, but the sac maintains its attachment at the periphery of the placenta.
Consequently, the yolk sac eventually
forms a fluid filled bag that surrounds the
embryo throughout gestation [Kaufman, 1992; Kaufman and Bard, 1999].
In contrast, the human embryo develops
from a flat disc with a ventrally located
yolk sac, and does not undergo a
190
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
dynamic turning process [Sadler and
Feldkamp, 2008]. Instead, the germ
layers maintain their same relative position and four body folds are formed on
the ventral surface of the embryo. These
four folds grow ventrally and eventually
fuse to form the umbilical ring. During
this process the yolk sac regresses and
eventually may only exist as a remnant by
mid gestation. Despite these differences,
the mouse still provides the best model to
probe the genetic causes of ventral body
wall closure defects given the resources
available for manipulating and mapping
its genome. In future, though, it would
be worthwhile to consider a survey
of embryogenesis in other mammalian
species to identify one that better
matches the process of normal human
body wall formation.
In conclusion, slow but steady
advances are occurring in our knowledge of ventral body wall closure in both
human and mouse. However, much still
needs to be done to achieve a basic
understanding of normal development
of this structure as well as its associated
pathology. Recommendations for future
analysis of body wall closure in vertebrate species are listed below:
1. Clear terminology–consistent with
the human nomenclature.
2. Increased awareness of the clinical
relevance of the animal data.
3. A better understanding of the normal
process of ventral body wall closure
and its pathologies in multiple species.
4. Mouse embryo dissections to leave
the umbilical cord intact and undamaged.
5. Detailed photo-documentation and/
or overt description of pathology.
6. A central repository for mouse
genetic models of ventral body wall
closure defects.
With the rising incidence of gastroschisis in the human population, the
cause of this birth defect should be
garnering increased attention. Perhaps
a necessary first step to achieve this goal
would be for those involved with body
wall closure defects in human and animal
model species to come together to
standardize terminology, share findings,
define issues, and advocate for resources
to tackle these prevalent but understudied birth defects.
ACKNOWLEDGMENTS
I am most grateful to Irene Choi
for preparing the illustrations used in
Figure 1. I thank Dr. Jarnail Singh,
Dr. Cory Brayton, Dr. Susan Little,
Dr. Ramona Skirpstunas, Dr. Bethany
Reid, Dr. Vida Melvin, Dr. Marcia
Feldkamp, and members of the Utah
Gastroschisis Workshop for stimulating
advice and discussion that have shaped
this perspective. I am also grateful to the
two anonymous reviewers for their
important clarifications and suggestions.
I have tried to reference the primary
literature when possible, but due to space
constraints I have also relied heavily on
previous review articles for overviews of
various topics. I apologize for any oversights in this regard.
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