Deficient Alk3-mediated BMP signaling causes prenatal
omphalocele-like defect
Jianping Sun
a
, Yi-Hsin Liu
b
, Hui Chen
a
, Manuel P. Nguyen
b
, Yuji Mishina
c
,
Jeffrey S. Upperman
a
, Henri R. Ford
a
, Wei Shi
a,
*
a
Developmental Biology Program, Department of Surgery, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, MS 35, Los Angeles, CA 90027, USA
b
Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
c
Molecular Developmental Biology Group, Laboratory of Reproductive and Developmental Toxicology, National Institutes of Health,
Research Triangle Park, NC 27709, USA
Received 7 June 2007
Available online 15 June 2007
Abstract
BMP signaling plays important roles in many embryonic developmental processes. Alk3 is one of two BMP type I receptors that
transduces BMP signal from the cell surface into cell. Conventional knockout of Alk3 resulted in early embryonic lethality around
E7.5–E9.5. In this study, we have generated embryonic mesoderm-specific Alk3 conditional knockout by crossing Dermo1-Cre and flo-
xed Alk3 mice. Abrogation of Alk3-mediated BMP signaling in this mouse resulted in severe defect of secondary ventral body wall for-
mation, replicating the omphalocele phenotype in human. Our finding suggests that Alk3 plays an essential role in the formation of
embryonic ventral abdominal wall, and abrogation of BMP signaling activity due to gene mutations in its signaling components could
be one of the underlying causes of omphalocele at birth.
Ó 2007 Elsevier Inc. All rights reserved.
Keywords: BMP; Alk3; Omphalocele; Ventral body wall
Ventral abdominal wall defects, including gastroschisis
and omphalocele, are congenital diseases that affect neo-
nates [1]. Omphalocele is characterized by the absence of
abdominal muscles, fascia, and skin; and in place of the
abdominal wall covering is a membrane consisting of peri-
toneum and amnion [2]. The abdominal contents, including
liver, stomach, and gut, often extrude ventrally through
this abnormally enlarged membranous sac, or called umbil-
ical ring. The incidence of omphalocele is reported to be 1
in 300–4000 births. Multiple genetic mutations and envi-
ronmental factors have been identified to be associated
with this defect. Moreover, omphalocele frequently occurs
in conjunction with other abnormalities, including cardiac
or genitourinary abnormalities, neural tube or skeletal
defects, as well as chromosomal anomalies, such as trisomy
13 and 18. Omphalocele may also be associated with Beck-
with–Wiedemann Syndrome [3,4]. However, the patho-
genic mechanism of omphalocele is still poorly
understood. Animal models of omphalocele are therefore
important to help identifying the key genetic mutations
and understanding the molecular pathogenic mechanisms.
During mouse embryonic development, following fold-
ing and turning of embryo, the ventral surface of the
embryo is covered by a primary body wall, consisting of
a thin epithelial membrane and loose mesenchyme, at early
embryonic stage of E9.5 [2]. This primary body wall per-
sists until E12, when a secondary body wall starts to form
to replace the membrane wall by somite-derived cells
migrating towards the ventral midline. Thus, the secondary
abdominal wall is composed of skin, muscle, abdominal
band derivatives and an inner epithelium. Disruption of
this secondary body wall formation results in defects
including omphalocele. The abnormal ventral body wall
0006-291X/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.bbrc.2007.06.049
*
Corresponding author. Fax: +1 323 671 3613.
E-mail address: wshi@chla.usc.edu (W. Shi).
www.elsevier.com/locate/ybbrc
Biochemical and Biophysical Research Communications 360 (2007) 238–243