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Development of the diaphragm and genetic mouse models of diaphragmatic defects.

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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 145C:109 – 116 (2007)
A R T I C L E
Development of the Diaphragm and Genetic
Mouse Models of Diaphragmatic Defects
KATE G. ACKERMAN* AND JOHN J. GREER
Improving our understanding of diaphragmatic development is essential to making progress in defining the
pathogenesis and genetic etiologies of congenital diaphragmatic defects in humans. As mouse genetic
technology has given us new tools to manipulate and observe development, a number of mouse models have
recently emerged that provide valuable insight to this field. In this article, we review our current understanding of
diaphragmatic embryogenesis including the origin of diaphragmatic tissue. We use rodent models to review the
muscularization of the diaphragm and review selected genetic models of abnormal muscularization. We also
review models of posterior diaphragmatic defects and discuss evidence for the pleuroperitoneal fold (PPF) tissue
contributing to the diaphragm. Finally, we discuss models of anterior and central hernias. It may be simplistic to
subdivide this review based on anatomic regions of the diaphragm, as evidence is emerging that defects in
different regions of the diaphragm in humans and in mice may be etiologically related. However, at this time we
do not have enough knowledge to make more mechanistic or genetic classifications though with time, genetic
progress in the field of diaphragm development will allow us to do this. ß 2007 Wiley-Liss, Inc.
KEY WORDS: CDH; diaphragm development; mouse genetic models
How to cite this article: Ackerman KG, Greer JJ. 2007. Development of the diaphragm and genetic
mouse models of diaphragmatic defects. Am J Med Genet Part C Semin Med Genet 145C:109–116.
INTRODUCTION
The diaphragm is a critical organ needed
to sustain life. Abnormal development of
the diaphragm in embryogenesis causes a
life-threatening problem for the newborn. Our current therapies are inadequate to sustain life, or life without longterm morbidity, in many of those
affected. Diaphragm defects are variable
in location, size, and type. Efforts
are underway to discover which genes
are required for normal development of
the diaphragm. One promising method
of discovery comes from the evaluation
of mouse models. Mice with mutations
in a number of genes have a variety of
diaphragmatic defects. Some of these
genes have been associated with diaphragmatic defects in humans, although
genetic etiologies for the common form
of isolated congenital diaphragmatic
hernia (CDH) are yet to be discovered.
Anatomy and Embryology/Origin
of Diaphragmatic Tissue
The diaphragm forms as a domed
structure in the human between 4 and
10 weeks of gestation and in the mouse
between embryonic days 10.5 and 15.5
(gestation ¼ 18.5 days). Until recently,
Kate G. Ackerman, M.D., is an Assistant Professor of Pediatrics at Harvard Medical School and
a member of the Division of Genetics at Brigham and Women’s Hospital and the Division of
Emergency Medicine, Department of Medicine at Children’s Hospital Boston. Dr. Ackerman is a
pediatric intensivist with post-doctoral research training in mouse genetics. Dr. Ackerman’s
research focuses on understanding the pathophysiology of diaphragmatic defects and pulmonary
hypoplasia in humans by investigating mechanisms of development in mouse models.
John J. Greer, Ph.D., is an Alberta Heritage for Medical Research Scientist and Professor of
Physiology at the University of Alberta. Dr. Greer’s research is in the area of perinatal
neuromuscular control and development. A major component of his research focuses on the
pathogenesis and etiology of congenital diaphragmatic hernia with a particular emphasis on
understanding the defect to the diaphragm.
*Correspondence to: Kate G. Ackerman, M.D., Division of Genetics, Brigham and Women’s
Hospital, Harvard Medical School New Research Bldg 464, 77 Avenue Louis Pasteur, Boston, MA
02115. E-mail: kackerman@rics.bwh.harvard.edu
DOI 10.1002/ajmg.c.30128
ß 2007 Wiley-Liss, Inc.
The diaphragm forms as a
domed structure in the human
between 4 and 10 weeks of
gestation and in the mouse
between embryonic days 10.5
and 15.5 (gestation ¼ 18.5 days).
interpretation of diaphragm development was based on inferences derived
from the anatomic appearance of the
diaphragm [Irish et al., 1996; Stolar,
1997]. Several advances in technology
allow us to evaluate and to alter expression patterns of genes important for
development, which combined with
knowledge gained from a teratogenic
model of rodent CDH [Costlow and
Manson, 1981] have enhanced our
understanding of normal and abnormal
diaphragm development.
The diaphragm has a characteristic
appearance which is similar in both
humans and rodents (Fig. 1). Muscularization is prominent along the perimeter
of the diaphragm, while the central
tendon region is not muscularized and
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ARTICLE
Figure 1. Normal mature human (A) and mouse (B,C) diaphragms. Photo (C) shows a close up of the anterior or ventral diaphragm.
Both human and mouse diaphragms have a central tendon region that is not muscularized (white arrows in photos A, B) with peripheral
muscularization and a distinct crural muscular region (Cr). The inferior vena cava and esophagus pass through the diaphragm (in A, B: large
black arrows—site of inferior vena cava, double arrows—site of esophagus). The pericardium is fused to the thoracic side of the human
diaphragm (P). The muscle in the anterior diaphragm forms two distinct bundles (photo C, white arrows). Herniation may occur between or
lateral to these bundles (in regions marked with black arrows).
has a distinct shape. The central tendon
remains attached to the liver by the
falciform and coronary ligaments.
Crural muscle in the posterior medial
diaphragm surrounds the esophagus and
inferior vena cava. All of the muscle of
the diaphragm is skeletal muscle and
is completely derived from migratory
muscle precursor cell populations
[Birchmeier and Brohmann, 2000].
Examination of mouse models has not
supported a previous hypothesis that
diaphragmatic musculature is derived
from the esophageal mesentery or ingrowth of muscle from the lateral body
wall.
Although the diaphragm consists of
different cell types (including those
comprising skeletal muscle, connective
tissue, mesothelium, blood vessels, and
nerves), it is probably completely
derived from the mesodermal tissue.
While the muscle cells originate from
paraxial mesoderm [Vasyutina and
Birchmeier, 2006], other tissues of the
diaphragm are derived from splanchnic
or somatic mesoderm [Sweeney, 1998].
The potential contributions from each
type of mesoderm to different regions of
the diaphragm have not been clearly
resolved. The splanchnic mesoderm
forms the heart and the tissue surrounding the gut while the somatic mesoderm
may form the pleuroperitoneal fold
(PPF), a structure believed to later
form the posterior diaphragm [Babiuk
et al., 2003]. A sub-type of the somatic
mesoderm, the septum transversum
mesoderm, contributes to the anterior
diaphragm [Sweeney, 1998; Babiuk
et al., 2003; Liu et al., 2003; Yuan
et al., 2003].
Diaphragm Muscle and Models
of Muscularization Defects
The muscle cells that migrate to the
diaphragm are derived from cervical
myotomes 3–5 (of 8), which are present
by week 6 of human development. These
somites are derived from paraxial
mesoderm. While trunk muscles (epaxial
muscles) are formed directly from dorsal
myotomes (epimeres), hypaxial muscle
groups are derived from the ventral
myotome (hypomeres). A portion of the
hypaxial muscle is migratory and it is
this group that gives rise to the muscles of
the diaphragm as well as the limb and the
tongue. A second, non-migratory hypaxial group extends ventrally to form the
intercostal and abdominal muscles including the external and internal obliques,
transversus abdominis, and rectus abdominis muscles [Sweeney, 1998].
The ventral dermomyotome cells
that populate the diaphragm can be
identified by the expression of Pax3, a
paired homeodomain transcription factor. In Pax3 mutant (Splotch) mice the
diaphragm muscle does not form [Li
et al., 1999]. Lbx1, a homeobox gene
that controls expression of other genes
required for normal muscle migration,
is also expressed by these migrating
muscle precursor cells and loss of Lbx1
affects the establishment of muscles
formed from these precursor cells.
Loss of Lbx1 decreases limb and
tongue muscularization but has the most
severe effect on the dorsal muscles of
the hind limb. Despite expression
in diaphragmatic muscle cells, loss of
Lbx1 does not affect diaphragm
musculature [Brohmann et al., 2000].
Thus, the transcriptional regulation of
muscle migration to different regions of
the body is specific.
Muscle precursors must delaminate
and migrate; these functions are largely
controlled by scatter factor/hepatocyte
growth factor (SF/HGF) and its receptor, c-Met. While c-Met is expressed in
migratory and non-migratory hypaxial
precursors, SF/HGF is restricted to
delaminating cells. SF/HGF is expressed
in the mesenchyme along the tracts of
migrating muscle cells [Dietrich et al.,
1999]. Embryos lacking expression of
c-Met (c-Met null) have amuscular
diaphragms, while embryonic lethality
of SF/HGF null mice has precluded
evaluation [Schmidt et al., 1995]. Mice
deficient in the gene, Fog2 have lack
of muscularization in the posterior
diaphragm in combination with a diffuse
muscular patterning defect. These mice
have abnormal and restricted patterns of
SF/HGF expression in the mesenchymal tissues posterior to the diaphragm in
a region where migratory muscle cells
temporarily reside prior to populating
the diaphragm [Ackerman et al., 2005].
Gab1 is essential for c-Met signaling, and
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
Gab1 null embryos also lack the
diaphragm muscle [Sachs et al., 2000].
Myogenic regulatory factors (MRFs)
are necessary for development of normal
skeletal muscle. These regulatory factors
belong to a group of basic helix–loop–
helix (bHLH) transcription factors
[Ludolph and Konieczny, 1995]. This
group, including MyoD, Myf-5, Mrf-4,
and Myogenin, along with the Mef2
family of proteins, coordinates regulation of gene expression during myogenesis in a complex fashion [Naya et al.,
1999; Berkes and Tapscott, 2005]. A
number of these factors are expressed
in developing diaphragm muscle and
mutations in some of these genes in mice
are associated with abnormal diaphragm
development. For example, Myogenin
null mice have amuscular diaphragms
[Tseng et al., 2000], while MyoD mutant
mice have thin diaphragms [Kablar et al.,
2003].
Correct muscularization of the
diaphragm requires complex coordination of precursor cells to delaminate,
migrate, target diaphragmatic tissue,
and differentiate; mutations in several
genes needed for these processes have
already been shown to cause aberrant
muscularization. Further investigation
Correct muscularization of the
diaphragm requires complex
coordination of precursor cells to
delaminate, migrate, target
diaphragmatic tissue, and
differentiate; mutations in
several genes needed for these
processes have already been
shown to cause aberrant
muscularization.
into mechanisms of diaphragmatic muscularization is important, as humans
with CDH may also have contralateral
diaphragmatic muscularization defects.
Human muscularization defects (often
referred to as eventrations) may be
111
diffuse or well circumscribed and may
be associated with herniation of abdominal contents into the chest (‘‘sac hernia’’) (further discussed in the article in
this issue by Dr. Pober). The developmental relationship between these
human muscularization defect phenotypes is unknown at this time, but
hopefully investigation in mouse models
will help to establish a developmentally
based classification (Fig. 2).
Development of the Posterior
Diaphragm and Models of
Posterior Hernias
Insight into the mechanisms of posterior
diaphragm development is critical to our
understanding of the most severe and
common forms of CDH in humans.
These hernias are often referred to
as Bochdalek hernias as they were
described in a publication by the professor of anatomy, Victor Alexander
Bochdalek [Irish et al., 1996]. Unfortunately, the original description of probable mechanism of rupture through a
Figure 2. Muscularization of the diaphragm. The diaphragm is muscularized by migratory muscle precursor cells. Photos A–D show
the normal progression of muscularization in whole diaphragms during development. Mutants with lack of normal muscle migration, like
c-Met null mice, have amuscular diaphragms (E). The central tendon is unmuscularized in the normal mature mouse diaphragm (F), however
mutations may induce over-muscularization. The ENU-induced mutation, Overgrown, causes muscle to almost completely cover the central
tendon (K. Ackerman, unpublished work). The Fog2 mutant mouse diaphragm does not develop musculature in the posterior diaphragm
bilaterally (H, posterior membranous diaphragm lacking normal muscle is marked with white arrows). Figures 2A–D reprinted from
J. Comp. Neurol. 391:275–292 with permission from the Wiley and Sons.
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
region of susceptibility in the lumbocostal triangle is probably only one of
the various putative mechanisms of
pathogenesis. Due to limitations in the
existing anatomic classification system of
CDH, different defects occurring in the
lateral, posterolateral, or posteromedial
regions of the diaphragm are all called
Bochdalek hernias (see accompanying
article by Dr Pober). These hernias are
often described as occurring through the
Bochdalek canal or foramen, although
the interpretation of the location and
boundaries of this canal varies widely
between practitioners. Posterior hernias
may have a sac around the herniated
organs. This sac is probably parietal
mesothelial tissue and/or the connective
tissue components of the diaphragm. It is
unknown why some posterior hernias
have a sac, while some do not. Of
note, virtually all anterior, central, and
anterior lateral hernias in humans have
a sac.
The posterior diaphragm, like other
regions of the diaphragm, may have
muscularization defects. These can be
diffused or well circumscribed and
cause no herniation or massive herniation. These defects are often referred to
as eventrations, although this term
is confusing because it technically
means herniation but is also used
to describe diaphragmatic elevation
associated with abnormal neurologic
function, but no anatomic defect. It is
unknown whether a muscularization
defect without herniation is part of
the same spectrum or mechanism of
pathogenesis as a sac hernia (technically,
a muscularization defect with large
herniation) or a hernia without a sac.
Evidence for these different phenotypes
existing within same families or
same syndromes suggests that they are
developmentally related [Rodgers and
Hawks, 1986; Stratton et al., 1993;
Slavotinek, 2004].
ARTICLE
The complete spectrum of phenotypes that occur in humans has not yet
been duplicated in the mouse; however
there are now an increasing number
of rodent posterior hernias that
may correspond to human defects
(Table I) including those with mutations or deletions in the COUP-TFII
(Chicken ovalbumin upstream promoter-transcription factor II, annotated as
Nr2f2) [Klaassens et al., 2005; Slavotinek
et al., 2006], Fog2 (Friend of Gata, 2)
[Ackerman et al., 2005], and Wt1
(Wilms tumor 1) genes [Scott et al.,
2005; Cho et al., 2006].
COUP-TFII is a member of the
nuclear receptor super family and is
essential for normal embryonic development. COUP-TFII null embryos die
prior to diaphragmatic embryogenesis
[Pereira et al., 1999], however a conditional deletion model has allowed
for discovery of a role in posterior
diaphragm development [You et al.,
TABLE I. Selected Genetic Mouse Models of Abnormal Diaphragm Development
Model
Defect
c-Met
Amuscular diaphragm [Babiuk and Greer,
2002]
Posterior hernia (no sac) [You et al., 2005]
COUP-TFII (Nkx 3.2 conditional model)
Fog2 (Zfpm2 lil/lil)
Gab1
Gata4
þ/
LOX
MyoD
Myogenin
MyoR/Capsulin
Pax3 (Splotch)
RARa/RARb2(retinoic acid receptors)
Slit3
Wt1
Posterior hernia (sac) [Ackerman et al.,
2005] muscle patterning defect
Amuscular diaphragm [Sachs et al., 2000]
Central hernia (sac) [Jay et al., 2006]
Central diaphragmatic rupture [Hornstra
et al., 2003]
Thin diaphragm, not functional [Kablar
et al., 1997]
Amuscular diaphragm [Tseng et al., 2000]
Posterior hernia (? sac) [Tseng et al., 2000]
Amuscular diaphragm [Li et al., 1999]
Compound receptor nulls have posterior
diaphragmatic hernias [Mendelsohn et al.,
1994]
Central midline hernia (sac) [Liu et al., 2003;
Yuan et al., 2003]
Posterior hernia [Clugston et al., 2006;
Kreidberg et al., 1993]
Human correlate
Unknown
Yes, cytogenetic hotspot 15q26.1-26.2
(DIH1, OMIM# 142340) (syndromic)
[Klaassens et al., 2005; Slavotinek et al.,
2006]
Yes, de novo mutation (non-syndromic)
[Ackerman et al., 2005]
Unknown
Suspected, cytogenetic Hotspot 8p23.1
(DIH2, OMIM#222400) [Lopez et al.,
2006; Slavotinek et al., 2006]
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown, suspected
Unknown
Yes, syndromic [Scott et al., 2005; Cho
et al., 2006]
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
COUP-TFII is a member of
the nuclear receptor super
family and is essential for
normal embryonic development.
COUP-TFII null embryos
die prior to diaphragmatic
embryogenesis, however a
conditional deletion model
has allowed for discovery
of a role in posterior
diaphragm development.
2005]. A majority of embryos with
deletion of COUP-TFII restricted to
mesenteric tissue had posterior diaphragmatic hernia. Although COUPTFII is expressed in primordial
diaphragmatic tissue, the central tendon,
and developing pulmonary mesenchyme, this model (Nkx 3.2 Cre expressing
cells) did not delete COUP-TFII in all
of these structures [You et al., 2005],
leaving open the possibility that the
diaphragmatic phenotype could be more
severe than what is observed in this
mouse model. COUP-TFII is believed
to play a role in human diaphragmatic
defects associated with other multiple
birth defects (syndromic CDH), as it is
one of the few genes located in a recently
narrowed cytogenetic hotspot for CDH
on chromosome 15q26.2 (discussed
further in the article in this issue written
by Dr. Pober).
Wt1 mutations are also associated
with posterior diaphragmatic defects.
These defects were first reported in
1993 [Kreidberg et al., 1993]; however
early embryonic lethality prevented
detailed analysis of the diaphragmatic
phenotype. Recently, expression of
Wt1 in primordial diaphragmatic tissue
(PPF) was characterized and structure
of this primordial tissue in Wt1 null
embryos was found to be abnormal
[Clugston et al., 2006]. Like COUPTFII and Fog2, Wt1 is also required
for the development of multiple organs
including the genitourinary system
[Kreidberg et al., 1993], the spleen
[Herzer et al., 1999], and the heart
[Kreidberg et al., 1993]. Mutations
and deletions of WT1 are associated
with congenital anomalies in humans,
including syndromes that may include
diaphragmatic defect [Natoli et al.,
2002; Scott et al., 2005; Cho et al.,
2006] and is discussed in the accompanying article by Dr. Slavotinek.
Fog2 is a transcription cofactor
for the GATA family of transcription
factors. Its interaction with Gata4 in vivo
is necessary for normal lung, diaphragm,
cardiac, and gonadal development
[Crispino et al., 1999; Tevosian
et al., 2002; Ackerman et al., 2006; Jay
et al., 2006]. Fog2 is expressed in
mesodermal tissues including the
pulmonary mesenchyme and mesothelium, and the PPF tissue (Fig. 3). Fog2
null mice die of cardiac defects prior to
diaphragm development, but mice
carrying a homozygote hypomorphic
mutation in Fog2 occasionally live
until late gestation. These mice have
posterior membranous diaphragms and
an abnormal pattern of muscularization
with no delineated central tendon. Fog2
is required for normal pulmonary development, as Fog2 null lungs explanted to
grow in vitro are hypoplastic and lack
normal lobar structure. Fog2 is the first
Fog2 is the first gene recognized
to be necessary for both primary
lung development and primary
diaphragm development
providing evidence for the
hypothesis that diaphragmatic
defects may be associated with
primary lung defects.
gene recognized to be necessary for both
primary lung development and primary
diaphragm development providing evidence for the hypothesis that diaphragmatic defects may be associated with
primary lung defects. A neonate who
died at birth with severe pulmonary
hypoplasia and a muscularization defect
113
in the eventration-sac hernia spectrum
was found to have a de novo stop
mutation in FOG2. In this patient, lung
size was smaller than expected based on
the extent of the diaphragmatic defect
further supporting the hypothesis that
the mutation in Fog2 caused both a
failure in primary lung development and
primary diaphragm development. Other
genes are now known to affect both
diaphragm and lung development
including COUP-TFII, Gata4, and retinoic acid signaling pathway genes [Mendelsohn et al., 1994; Malpel et al., 2000;
Ackerman et al., 2006; Jay et al., 2006]. It
is probable that some posterior defects
arise from genetic mutations that do not
independently affect lung development,
while others affect the development of
both organs (and often the heart as well).
Once more human causes are identified;
it may be possible to predict risk of
pulmonary and cardiac sequelae based
on the specific genetic mutation.
Although there is ample evidence to
support the hypothesis that similar
developmental genes are needed for
both lung and diaphragm development
and that both structures may be primarily affected in CDH, there is insufficient
evidence to support the hypothesis that
defects in lung development lead to
secondary defects in diaphragm development. The most compelling evidence
against this latter hypothesis is that mice
lacking lung development (FgF10null/null)
have normal diaphragms [Babiuk and
Greer, 2002].
The tissues that contribute to
the posterior diaphragm are referred to
as the PPFs and the post hepatic
mesenchymal plate tissue (PHMP).
Although it is unclear whether these
structures represent different sections of
the same mesodermal tissue, the terms
are used interchangeably by different
investigators [Greer et al., 2000a; You
et al., 2005] to describe tissue contributing to the diaphragm. The PPFs are
largest and most evident in the embryonic thorax at the level of the forelimb
just prior to diaphragm development
(e11.5 in the mouse). The PPF has been
shown to be the precursor tissue of the
diaphragm in studies of teratogenically
induced CDH [Greer et al., 2000b].
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ARTICLE
Figure 3. Primordial diaphragmatic tissue and gene expression. The pleuroperitoneal fold (PPF) tissue contributes to the posterior
diaphragm and is visualized in the mouse thorax at e11.5 as two triangular structures (A, black arrows). The phrenic nerves (marked with *)
innervate the diaphragm and are surrounded by PPF tissue. Three-dimensional reconstruction of the PPF in a normal mouse embryo
(B) and in a nitrofen exposed mouse embryo (C). The nitrofen mutant PPF lacks tissue in the posterior and caudal region of the PPF.
Immunohistochemical staining of the PPFs (D,E). COUP-TFII and Pax 3 (marker for migratory muscle cells) are expressed in different
cells of the PPF (D, COUP-TFII labeled green and Pax3 labeled red) while COUP-TFII and Wt1 share some co-expression in the PPF
(E, COUP-TFII labeled green, Wt1 labeled red, double labeled cells appear yellow). Genetically engineered mice carrying LacZ reporter
genes show Wt1 expression (F) and Fog2 expression (G) in the PPF tissue. Wt1 is expressed in the lateral PPF while Fog2 expression is diffuse.
Figure 3B-E reprinted from Am. J. Pathol. 2006 169: 1541–1549 with permission from the American Society for Investigative Pathology.
This model will be discussed in more
detail in the article by Dr. Kling and
Dr. Schnitzer, but in short, embryos
exposed to the herbicide nitrofen in
utero develop posterior diaphragmatic
defects. Examination of the structure of
the PPF in these embryos reveals tissue
loss in the rostral and lateral aspects. This
morphologically abnormal structure
resembles those observed in vitamin
A deficient embryos that are also predisposed to developing posterior hernias. It
should be noted that one group has
suggested that nitrofen-induced PPF
defects create posteromedial hernias
rather than posterolateral hernias
[Fisher and Bodenstein, 2006]. This
was concluded from a two-dimensional
computer simulation of the muscular
diaphragm from a single type of
nitrofen-induced PPF defect. However,
there are clear examples of defects in the
lateral regions of the diaphragm in the
nitrofen model [Allan and Greer, 1997].
Modeling is required that focuses on the
three-dimensional mesenchymal nonmuscular substratum and takes into
consideration the full range of PPF
defects observed in the nitrofen model.
Currently known genes expressed
in PPF tissue include those restricted to
migratory muscle precursor cells (Pax3),
and those needed for normal diaphragmatic development (Fog2, COUP-TFII,
Wt1) which are not expressed in muscle
cells. There is co-localization of Wt1 and
COUP-TFII protein in the PPF,
especially along the dorsal mesothelial
surface, and this expression does not
co-localize with the muscle precursors
labeled with Pax3 [Clugston et al.,
2006]. Fog2 is expressed diffusely in the
PPF and also does not co-localize with
muscle precursor markers (Fig. 3). An
interaction between Wt1 and COUPTFII has not been established, and it
remains unclear how these genes might
work together to promote normal
diaphragmatic development.
Models of Central and
Anterior Hernias
Diaphragmatic hernias and muscularization defects may also occur in the
anterior or central diaphragm. Most
anterior defects are referred to as
Morgagni defects in humans as these
and other anterior defects were described by Giovanni Battista Morgagni in the
1700s [Irish et al., 1996]. The musculature of the anterior or ventral and
midline diaphragm is attached to the
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
sternum and xyphoid process. This
anterior muscle is distinct from the
peripheral muscle and forms two distinct
muscle bundles. The regions medial and
lateral to these muscle bundles are
potential areas of weakness predisposed
to herniation. This anterior diaphragmatic anatomy is shown in Figure 1.
Historically, Morgagni hernias were
described as occurring lateral to these
anterior muscles on the right side.
Hernias may also occur centrally (subxyphoid or retrosternal) or on the left
side (Larrey hernia). Although they may
represent different types of hernias, most
anterior hernias are simply classified as
being Morgagni hernias in humans
[Salman et al., 1999; Loong and Kocher,
2005]. It is unknown at this time
whether mouse models of anterior
hernias correspond to anteriorly located
human diaphragmatic defects.
Mouse models of anterior and/or
central diaphragmatic defect include
those with mutations in Slit3, Gata4,
and lysyl oxidase (LOX). Slit genes (Slit1,
Slit2) are expressed prominently with
the CNS, where they bind to Robo
receptors to act as axonal guidance
molecules. In contrast, Slit3 is expressed
predominantly in other tissues including
the lung and the diaphragm [Yuan et al.,
2003; Yuan et al., 1999]. To investigate
in vivo functions for Slit3, a null
mutation was introduced into Slit3 in
mice by targeted mutagenesis in
embryonic stem (ES) cells. Slit3 null
mice develop a central and midline
diaphragmatic defect that ranges in
location from being very anterior to
involving a major portion of the central
tendon. In these mice, a circular portion
of the anterior tendon is significantly
thinner than in wild-type mice and the
connective tissue appears disorganized.
The enlarging liver distends and ultimately herniates through the weakened
area of the tendon [Liu et al., 2003;
Yuan et al., 2003]. This phenotype may
be similar to the very rare ‘‘septum
transversum’’ type of CDH or the anterior defects associated with Pentalogy
of Cantrell [Wesselhoeft and DeLuca,
1984] but a genetic association between
SLIT mutations and human diaphragmatic defect has not yet been found.
A similar defect occurs in approximately 30% of mice heterozygous for a
mutant allele of Gata-4 [Jay et al., 2006],
a transcription factor that interacts with
Fog2. These mice also have herniation of
the liver through the central diaphragm.
It is not known whether Gata4 mediated
diaphragm development is Fog2 dependent, although it is probable as Fog2–
Gata4 interactions are necessary for the
development of other organs including
the heart, gonads, and lungs [Crispino
et al., 2001; Tevosian et al., 2002;
Ackerman et al., 2006]. Early embryonic
lethality in Gata4 and Fog2 null mice
makes comparison of phenotypes and
mechanism of diaphragmatic development difficult, and further investigation
is needed, perhaps utilizing conditional
gene deletion models.
An additional model is that of
diaphragmatic rupture of the central
tendon due to deficiency in the enzyme,
lysyl oxidase (LOX). Lox targeted
null mice die with ruptured arterial
aneurysms and diaphragms secondary
to defects in collagen development
[Hornstra et al., 2003]. Although defects
in the diffuse collagen structure may
result in diaphragmatic herniation,
these are currently not thought to be
developmentally associated with most
neonatal CDHs.
CONCLUSIONS
Defining the normal embryogenesis of
the diaphragm is critical to advancing
our understanding of diaphragmatic
defects in animal models and in humans.
The study of diaphragm and other organ
development can be achieved using
genetic models. CDH has naturally
occurred and has a suspected genetic
etiology in some families of monkeys,
pigs, and dogs [Bush et al., 1980;
Valentine et al., 1988; Ohkawa et al.,
1993]; however their use for studying
organ development in the laboratory is
limited. Genetic mouse models provide
excellent tools for doing this, and there
are now multiple genes known to be
important for diaphragm development
as well as primary lung, and heart
development. Since humans with
CDH often have lung, cardiac, and
115
other defects, the discovery of genetic
pathways controlling development independently in the thoracic and upper
abdominal regions of the embryo or
fetus will result in a better understanding
of the disease. Hopefully, this will lead to
the discovery of therapeutic regimens to
treat co-morbid lung, cardiovascular,
and gastrointestinal disease in CDH
patients.
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