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Ventral abdominal wall dysmorphogenesis of Msx1Msx2 double-mutant mice.

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Mouse House
THE ANATOMICAL RECORD PART A 284A:424 – 430 (2005)
Ventral Abdominal Wall
Dysmorphogenesis of Msx1/Msx2
Double-Mutant Mice
HIDENAO OGI, 1,2 KENTARO SUZUKI, 1 YUKIKO OGINO, 1
MIKA KAMIMURA, 1 MAMI MIYADO, 1 XU YING,1 ZUNYI ZHANG,3
MASANORI SHINOHARA,2 YIPING CHEN, 3 AND GEN YAMADA1*
1
Center for Animal Resources and Development, Graduate School of Medical and
Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
2
Department of Oral and Maxillofacial Surgery, Graduate School of Medical
Sciences, Kumamoto University, Kumamoto, Japan
3
Department of Cell and Molecular Biology, Tulane University,
New Orleans, Louisiana
ABSTRACT
Msx1 and Msx2 genes encode the homeodomain transcription factors.
Several gene knockout mice and expression studies suggest that they possess functionally redundant roles in embryogenesis. In this study, we revealed that Msx1 and Msx2 were expressed during ventral body wall formation in an overlapping manner. Msx1/Msx2 double-mutant mice
displayed embryonic abdominal wall defects with disorganized muscle layers and connective tissues. These findings indicate that Msx1 and Msx2 play
roles in concert during embryonic ventral abdominal wall formation.
©
2005 Wiley-Liss, Inc.
Key words: Msx gene; homeobox gene; body wall; congenital hernia;
embryogenesis; mouse
During mouse development, the ventral body wall consisting of thin epithelial membrane and loose mesenchyme is formed after the primary body wall develops. The
generation of the mature secondary ventral body wall is
observed after 12.0 days postcoitum (dpc). Around these
stages, the entire ventral body wall remains open and
visceral organs are exposed. Later in development, embryonic body wall mesenchyme is mainly contributed by entering cells derived from somites. Somite-derived cells enter into primary body wall developing to distal (ventral)
side of embryos forming the secondary body wall. The
secondary body wall of the abdomen includes skin, muscle,
and abdominal band derivatives (Christ et al., 1983; Kaufman, 1999; Brewer and Williams, 2004b).
Up to now, several works by gene knockout mice have
been issued to explain the basis of the pathogenesis of
body wall defects related with some congenital human
birth defects. In particular, mutations identified in some
of the genes for transcription factors, cell signaling molecules, and proteases are associated with various degrees of
body wall developmental abnormalities (Hasty et al.,
1993; Nabeshima et al., 1993; Suzuki et al., 1996; Zhang et
al., 1996; Eggenschwiler et al., 1997; Roebroek et al., 1998;
Tremblay et al., 1998; Manley et al., 2001; Dunker and
©
2005 WILEY-LISS, INC.
Krieglstein, 2002; Brewer and Williams, 2004a, 2004b).
However, comprehensive and integrated understanding of
molecular genetic cascades for the development of body
walls awaits further analyses.
The vertebrate Msx homeobox gene family contains
three members, two of which (Msx1 and Msx2) have been
well studied with respect to their expression patterns and
Grant sponsor: Grant-in-Aid for Scientific Research on Priority
Areas (1,2), General Promotion of Cancer Research in Japan
(11177101), Mechanisms of Sex Differentiation (16086208);
Grant sponsor: the 21st Century COE Research Program and
Child Health and Development (14C-1), the Ministry of Health,
Labor and Welfare.
*Correspondence to: Gen Yamada, Center for Animal Resources and Development, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan. Fax: 81-96-373-6560.
E-mail: gen@kaiju.medic.kumamoto-u.ac.jp
Received 31 August 2004; Accepted 20 December 2004
DOI 10.1002/ar.a.20180
Published online 31 March 2005 in Wiley InterScience
(www.interscience.wiley.com).
VENTRAL ABDOMINAL WALL DYSMORPHOGENESIS
functional properties. These genes encode closely related
homeoproteins that function as transcriptional repressors
through interactions with components of the core transcription complex as well as other homeoproteins (Bendall
and Abate-Shen, 2000). Both Msx1 and Msx2 are expressed in an overlapping manner spatially and temporally during development in discrete regions of the facial
primordia, limbs, neural tube, and other embryonic regions (Davidson, 1995; Satokata et al., 2000; Zhang et al.,
2002; Alappat et al., 2003; Cheng et al., 2004). It has also
been demonstrated that Msx genes can regulate cellular
proliferation and differentiation (Pavlova et al., 1994;
Chen et al., 1996, 2000; Ferrari et al., 1998; Dodig et al.,
1999). In this study, we analyzed Msx1/Msx2 double-mutant embryos and revealed their abnormal abdominal wall
development with aberrantly aligned connective tissues
and body wall muscles.
MATERIALS AND METHODS
Msx1/Msx2 Double-Mutant Embryos
Mice carrying a targeted deletion of the Msx1 gene or
the Msx2 gene were described previously (Satokata and
Maas, 1994; Satokata et al., 2000). Homozygous mutant
embryos were obtained by heterozygote mating. Msx1/
Msx2 double-mutant embryos were obtained by double
heterozygote mating. The genotype of each embryo was
identified by PCR as previously described (Satokata and
Maas, 1994; Satokata et al., 2000). Laboratory animal
care and animal use for the present study were performed
under the guidance of animal researches of the Tulane
and Kumamoto University.
In Situ Hybridization
Whole-mount in situ hybridization for gene expression
analysis was performed with digoxigenin-labeled probes
by standard procedures (Wilkinson, 1992) with probes for
Msx1 and Msx2 (Zhang et al., 2003).
Histological Analysis
Embryos were fixed in 4% paraformaldehyde. They
were dehydrated in graded ethanol, embedded in paraffin,
and sectioned at a thickness of 5.0 ␮m. Sections were
stained with hematoxylin and eosin (H&E) by standard
procedures. Connective tissue was stained with Masson’s
trichrome technique (Muto Pure Chemicals).
RESULTS
Msx1 and Msx2 Are Expressed in Primary Body
Wall During Development
Several expression and gene knockout mice studies suggest that Msx1 and Msx2 possess functionally redundant
roles in embryogenesis (Satokata et al., 2000; Alappat et
al., 2003; Zhang et al., 2003). As for possibly interacting
genes with Msx genes, Bmp genes have been suggested as
interacting in genetic cascades with Msx genes. In fact,
orchestration of regulatory genes involved in Bmp signaling has been reported for organogenesis such as tooth,
palate, and heart development (Chen et al., 1996; Bei and
Maas, 1998; Zhang et al., 2002; Brugger et al., 2004). Bmp
genes are expressed in developing body wall and they are
required for normal body wall development (Suzuki et al.,
1996; Funayama et al., 1999; Sudo et al., 2001). Hence, we
analyzed the spatial and temporal expression pattern of
425
Msx1 and Msx2 during abdominal body formation and
performed histological studies on abdominal body walls of
Msx1/Msx2 double-mutant embryos.
In early embryogenesis, ventral body wall develops first
as the primary body wall. In mouse embryos, the primary
body wall lacks somite derived tissues before 12.0 dpc, but
the secondary body wall is formed afterwards by somite
derived cells after 12.0 dpc. Primary ventral body wall
develops distally, which engulfs visceral organs in the
coelom accompanied with the growth of the visceral organs (Kaufman, 1999; Gilbert, 2003; Brewer and Williams, 2004a, 2004b). The Msx1 and Msx2 were expressed
in the developing primary body wall at 9.5 dpc (Fig. 1A
and B). They were mainly expressed in the developing
somatopleure in earlier stages such as at 8.0 dpc (data not
shown). Both Msx1 and Msx2 were expressed in overlapping manner at the level of the trunk in the developing
primary body wall mesenchyme as shown by the abdominal transverse sections (Fig. 1C and D). Msx1 was expressed in the restricted region in the body wall anteroposteriory at 11.0 dpc (Fig. 1E). This region of the body
wall corresponded to the periumbilical region surrounding
the umbilical cord. In contrast, Msx2 was expressed
broader than Msx1 anteroposteriory at 11.0 dpc (Fig. 1F).
The level of Msx1 was drastically reduced at 12.5 dpc
embryos and only faint signals were observed around the
umbilical ring (data not shown). In contrast, the signal of
Msx2 was decreased rapidly after 11.0 dpc (data not
shown). The above expression patterns prompted us to
examine the phenotypes of the body wall formation in the
corresponding gene knockout mice.
Dysmorphogenesis of Abdominal Body Wall in
Msx1/Msx2 Double-Mutant Embryos
The developmental time course of the abdominal body
wall formation of the Msx1/Msx2 double-mutant embryos
were examined histologically. The ventral body wall develops to the midline and most of the visceral organs,
including stomach, were engulfed in the coelom at 12.5
dpc in wild-type embryos (Fig. 2A and C). Prominent hypoplasia of the abdominal body wall was observed in
Msx1/Msx2 double-mutant embryos. Abdominal body wall
elongation and subsequent engulfment of the visceral organs were not observed particularly in the distal abdominal wall region of the double mutant embryos (Fig. 2B
and D). The developing abdominal mesenchymal tissues
were observed in distal regions of the body wall in wildtype mice (Fig. 2C, white arrowheads). In contrast, the
developing abdominal wall was markedly thinner and hypoplastic and its distal (ventral) development was defective with only thin amnionic membrane locating in the
ventral side of Msx1/Msx2 double-mutant embryos (Fig.
2D). In normal embryogenesis, three muscle layers develop composed by transversus abdominis muscle, internal oblique muscle, external oblique muscle within the
abdominal muscle layers at 14.5 dpc (Fig. 2G, black arrowheads). In contrast to such distally elongated muscle
development, misarranged muscular tissues were observed in lateral abdominal regions of the Msx1/Msx2
double-mutant embryos (Fig. 2H, black arrowhead).
Msx1/Msx2 double-mutant embryonic body wall did not
reach to the ventral (distal) side (Fig. 2F). The collagen
fibers in the connective tissues of the abdominal regions
were arranged in a regular parallel pattern in the wildtype specimens (Fig. 2I). In contrast, Msx1/Msx2 double-
426
OGI ET AL.
Fig. 1. Gene expression pattern of Msx1 and Msx2. Whole-mount in
situ hybridization for gene expression (A–F) and their expression at the
abdominal level (C and D). Msx1 and Msx2 were expressed in overlapping manner in the primary body wall mesenchyme including abdominal
region at 9.5 dpc (A–D, arrowheads). The region of Msx1 expression was
expressed narrower anteroposteriory than that of Msx2 as indicated by
white arrowheads at 11.0 dpc (E and F arrowheads). FL, fore limb; UC,
umbilical cord; T, tail; HL, hind limb; GT, genital tubercle. Scale bar ⫽
500 ␮m (A, B, E, and F); 100 ␮m (C and D).
mutant embryos displayed spongy and highly disorganized alignment of collagen fibers in the connective tissue
of the abdominal body wall (Fig. 2J). Cutaneous structures
including cutaneous maximus muscle and connective tissue of the dermis displayed mostly normal architecture in
Msx1/Msx2 double-mutant embryos (Fig. 2E and F, black
arrow). Null mutant of each gene did not display malformations (data not shown). In sum, Msx1/Msx2 doublemutant embryos displayed abnormal development of the
connective tissues and muscular tissues in abdominal
body wall resulting in severe hernia of the visceral organs.
formation of the muscles takes place in several characteristic steps as shown by chick embryologic studies (Christ
et al., 1983). The ventral somatic buds which consist of
myotome and dermomyotome cells enter the somatopleure
of chick embryos (Christ et al., 1983). Thus, in contrast to
limb muscle precursors, muscle precursors for the abdominal muscles are basically considered not to migrate to
their target site in chick embryos. The murine embryonic
body wall of the abdomen is composed by mesenchymal
connective tissues and somite derived muscles at 14.5 dpc
(Christ et al., 1983; Kaufman, 1999; Gilbert, 2003; Brewer
and Williams, 2004a, 2004b).
Several mutant mice with body wall abnormalities have
been extensively analyzed (Qu et al., 1997; Manley et al.,
2001; Dunker and Krieglstein, 2002; Brewer and Williams, 2004a, 2004b). However, the molecular mechanism
of mammalian body wall formation and pathogenesis of
body wall abnormalities are still poorly understood.
Msx genes have been reported to play roles during various organogenesis (Bei and Maas, 1998; Satokata et al.,
2000; Zhang et al., 2003). In the current report, histological description of the abdominal body wall defects of
DISCUSSION
In early embryogenesis, ventral body wall develops first
as the primary body wall consisting of thin epithelia and
loose mesenchymes. In the abdominal region of the embryonic body wall, somite-derived cells participate in
many embryonic structures. Somites form various muscles and abdominal wall and the dermis of the dorsal skin.
In mouse embryos, the primary body wall lacks somitederived tissues before 12.0 dpc, but the secondary body
wall is formed afterwards by somite derived cells. The
VENTRAL ABDOMINAL WALL DYSMORPHOGENESIS
427
Fig. 2. Lateral view of the embryos (A and B) and transverse sections
with H&E staining (C and D) of the abdominal wall at 12.5 dpc. Masson
staining of abdominal wall (E and F) and photographs of higher magnifications at 14.5 dpc (G–J). Compared to the wild-type embryos (E, G, I),
body wall hypoplasia including disorganized muscle layers (G and H,
black arrowheads) and connective tissues (I and J) were observed in
Msx1/Msx2 double-mutant embryos. Cutaneous structures were not
markedly disorganized (E and F, arrows). V, ventral side; D, dorsal side;
am, amnion; eo, external oblique muscles; io, internal oblique muscles;
ta, transversus abdominis muscles; St, stomach. Scale bar ⫽ 60 ␮m (A
and B); 200 ␮m (C and D); 500 ␮m (E and F); 250 ␮m (G and H); 20 ␮m
(I and J).
Msx1/Msx2 double-mutant mice was presented. The phenotypes reflect spatial and temporal expression of Msx1
and Msx2 genes. Msx1 and Msx2 genes are known to
encode closely related homeodomain containing transcriptional repressors (Bendall and Abate-Shen, 2000). Several
abdominal body wall abnormalities have been reported in
gene knockout mice for homeobox-containing genes. Alx4,
a member of the aristaless family of homeobox genes, has
been reported as displaying abdominal body wall defects
in its mutants. Possible interactions between Alx genes
and Msx genes have yet been unelucidated. However, recent double-mutant analysis for Alx4 and Msx2 genes
suggested their interaction in organogenesis such as during heart, lung, and diaphragm formation (Antonopoulou
et al., 2004). Alx4 is expressed in an overlapping manner
in the prospective ventral body wall region with Msx1 and
Msx2 genes from 9.0 until 11.5 dpc (Qu et al., 1997).
Ventral abdominal wall is markedly thinned both in Alx4
(Qu et al., 1997) and Msx1/Msx2 double knockout mutants. While the phenotypes of Msx1/Msx2 double-mutant
428
OGI ET AL.
mice became visible from 12.5 dpc, ventral body wall defects of Alx4 mutant mice become first apparent approximately at 15.5 dpc (Qu et al., 1997). Mechanisms for
different abdominal body wall phenotype onset in both
mutants await further analysis.
Hox gene knockout mice also displayed various degrees
of body wall abnormalities. Both Hoxb2 mutant mice and
Hoxb4 mutant mice have defects in primary body wall
development for the chest regions (Manley et al., 2001). It
has been known that Hox genes could be regulated by
retinoic acid (RA) indicated by various experimental systems (Kessel and Gruss, 1990; Yashiro et al., 2004). As for
another retinoic acid-inducible transcription factor, Ap-2,
the AP-2␣ knockout mice also exhibit severe ventral body
wall closure defects (Schorle et al., 1996; Zhang et al.,
1996; Brewer and Williams, 2004b). These results raise
questions about possible regulatory cascades among such
genes for ventral body wall formation.
Msx genes may modulate the regulation of type I collagen possibly affecting the formation of extracellular matrix (ECM) development (Dodig et al., 1996; Alappat et al.,
2003). Tgf-␤ genes are members of the Tgf-␤ super family
and they elicit cellular responses via signaling through
specific type I and type II serine/threonine kinase receptors. TGF-␤s are known to promote matrix deposition by
increasing the expression of fibronectin and collagens and
also by upregulating inhibitors of matrix proteases (Grotendorst, 1997; Hocevar and Howe, 2000). Tgf-␤2/Tgf-␤3
double-mutant mice display severe ventral body wall malformations (Dunker and Krieglstein, 2002). The body wall
muscles of these mutants did not reach to the ventral side
and their thickness was reduced (Dunker and Krieglstein,
2002). Previous reports and the current analysis indicate
that both Msx1/Msx2 double-mutant embryos and Tgf-␤2/
Tgf-␤3 double-mutant embryos exhibit spongy connective
tissues with loosely organized pores and mesh-like collagen fiber bundles. Further analyses including marker
analysis on the relationships with Msx genes and Tgf-␤
genes are required.
Three layers of developing muscles, including transversus abdominis muscle, internal oblique muscle, and external oblique muscle, are derived from the lateral side of
dermomyotome, which has been suggested to secure the
strength of the body wall around 14.5 dpc (Kaufman, 1999;
Sadler, 2000; Gilbert, 2003). Various developmental studies have suggested a possible involvement of regulatory
factors, including secretory signals regulating dermomyotome formation from the lateral plate (Cossu et al., 1996;
Pourquie et al., 1996; Dietrich et al., 1998; Alvares et al.,
2003). Although this study does not provide information
about the involvement of Msx genes related with regulatory mechanisms, these possibilities may be worth pursuing with marker studies. It was shown that Bmp4 was
expressed in the developing primary body wall and to
regulate MyoD expression and the generation of hypaxial
myotomes (Pourquie et al., 1996). Various reports on other
organogeneses suggested relationships between Msx1,
Msx2, and Bmp4 genes (Brugger et al., 2004). Msx1 and
Msx2 have also been suggested as factors necessary for
proper Bmp4 expression in organogenesis (Semba et al.,
2000; Zhang et al., 2002). These data might imply a possibility of the perturbed signaling including genes, e.g.,
Bmps during the abnormal primary body wall formation
in Msx1/Msx2 double mutants.
Aberrant muscle formation reported in this study could
also be derived from the Msx1 and Msx2 expression in the
developing dermomyotome. The current in situ gene expression analysis did not detect Msx1 or Msx2 expression
in the developing dermomyotome per se in contrast to the
previous report utilizing LacZ knock-in mice (Houzelstein
et al., 1999). Such discrepancy about the expression levels
may be due to the sensitivity of detection. The possible
involvement of Msx1 and Msx2 genes in this differentiation process should be analyzed further.
The Pax3 gene could also be listed as a candidate interacting with Msx genes during body wall formation. It has
also functions during abdominal body wall and limb muscle formation (Tremblay et al., 1998). The Pax3 gene is an
early marker for the entire paraxial mesoderm and its
dorsal derivative, the dermomyotome. Later, its expression becomes restricted to the lateral dermomyotome and
to the migratory muscle precursors giving rise to the hypaxial musculature (Dietrich et al., 1998). Pax3 expression may be involved as a trigger for the myogenic program and induces expression of MyoD in paraxial
mesoderm explants (Epstein et al., 1995; Maroto et al.,
1997; Bendall et al., 1999). Ectopic coexpression of Msx1
and Pax3 neutralizes the effect on MyoD and MSX1 protein interacts with Pax3 in vitro, thereby inhibiting DNA
binding by Pax3 (Bendall et al., 1999). The regulation of
Pax3 could affect Msx2 expression in cardiac neural crest
(Kwang et al., 2002). In the mutant mice with disrupted
Pax3 function (Sploch), the three layers of abdominal
muscles were present laterally, but they displayed a disorganized array of fibers, and their development did not
progress ventrally (Tremblay et al., 1998).
In human, absence of abdominal muscles generally results in syndromes with exposed visceral organs and it has
been speculated as induced by multifactorial genetic elements. The majority of human body wall malformations
are non-syndromic and their mechanism of pathogenesis
is unclear. Hence, comprehension of normal and abnormal
development of body wall formation depends still largely
on genetic studies utilizing various gene knockout mouse
models. The current study offered histological data of the
abdominal dysmorphology of Msx1/Msx2 double-mutant
embryos. Involvement of Msx1/Msx2 for human birth defects as part of the plausible genetic elements should be
further pursued.
ACKNOWLEDGMENTS
The authors thank Drs. Kathy Svoboda, Hubert Schorle,
Virginia E. Papaioannou, Janet Rossant, Chi-chung Hui,
Gail Martin, Frits Meijlink, Brigid Hogan, Uli Ruether,
Roger Markwald, Susanne Dietrich, Yoshihiro Komatsu,
Hironori Katoh, Sho Ohta, Maria A. Ros, Gary C. Schoenwolf, and Anne M. Moon for reagents and/or suggestions
and Shiho Kitagawa for assistance.
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