Biomedical Engineering Reference
In-Depth Information
transducers from the BMP receptor complex
following
or lethality. The complete ablation of BMP-
2
by homologous recombination resulted in
embryonic lethality when bred to homozygos-
ity [
receptor
transphosphorylation
events. Smads
interact with types I
and II BMP receptors and are subsequently
phosphorylated by the type I receptor within
their COOH-terminus at the conserved SSXS
motif [
1
,
5
, and
8
]. These animals had distinct cardiac
defects consistent with the expression pattern-
ing of BMP-
228
in the extraembryonic mesoderm
and promyocardium [
2
]. They are then rapidly released
from the receptor and subsequently interact
with a common mediator Smad (co-Smad).
Smad
207
is expressed
in a variety of embryonic nonskeletal epithe-
lial and mesenchymal tissues known to play
important roles in morphogenesis [
228
]. BMP-
2
is the only known co-Smad that signals
in both the BMP and the TGF-
4
]. For
example, during limb development high levels
of transcripts were found in the ventral ecto-
derm and apical ectodermal ridges of the
developing limb buds. In addition, BMP-
139
β
transduction
pathways [
]. The R-Smad and the co-Smad
proteins form active hetero-oligomeric com-
plexes, which can then translocate to the
nucleus and regulate the transcription of spe-
cifi c downstream genes. The nuclear localiza-
tion of the Smad complexes is dependent on
nuclear localization signals present on Smad
207
2
expression was detectable in the developing
heart, whisker follicles (ectodermal placodes),
tooth buds (epithelial buds, dental papillae,
and odontoblasts), and craniofacial mesen-
chyme [
.
Consequently, this protein displays constant
nuclear-cytoplasmic shuttling and is capable
of autonomous nuclear import and export
[
4
]. Although other studies have vali-
dated the importance of BMP-
139
during a wide
array of mesodermal developmental processes,
the protein also plays important roles in regu-
lating the postnatal development of mesenchy-
mal skeletal tissues [
2
]. The third class of Smad proteins consists
of the inhibitory Smads (I-Smads), Smad
218
6
and
Smad
, which exert their inhibitory effect by
binding to the type I receptor and competing
with the R-Smads for binding to the phosphor-
ylated type I receptor.
All Smads share two conserved regions
termed Mad homology domains
7
]. In animals with a
homozygous deletion of the mature coding
region of the BMP-
176
gene, development fails at
an extremely early stage. The mice fail to
develop the necessary primordial germ cells
(PGCs) to form a functional embryo [
4
1
(MH
1
) and
123
].
2
is found in the N-terminal
portion of the protein, whereas MH
(MH
2
). MH
1
Lawson et al. have shown that BMP-
pro-
moter-driven LacZ expression in embryos
prior to gastrulation results in BMP-
4
is in the
C-terminal portion, with a linker region of
variable length and amino acid sequence sepa-
rating the two domains [
2
expres-
sion in the extraembryonic ectoderm, followed
by expression in the extraembryonic meso-
derm [
4
domain
contains protein-protein interaction sequences
and is important in R-Smad/co-Smad oligo-
merization. The MH
150
]. The MH
2
]. These authors concluded that the
initiation of the germ line in the mouse was
dependent on secreted BMP-
123
domain seems to carry
specifi c DNA-binding sequences necessary to
act at the DNA level in the discrimination of
gene regulation. However, a putative “Smad
consensus sequence” has yet to be determined
[
1
signals from the
previously segregated, extraembryonic, troph-
ectoderm lineage. This places BMP-
4
function
at one of the earliest stages of development
[
4
]. However, BMPs do not appear to act
individually but in a coordinated network. For
example, the above-mentioned PGC cell gen-
eration is directed by more than just BMP-
123
107
].
.
In fact, one study has demonstrated that BMP-
2
4
2.2.2.2 BMPs and Developmental
Regulation
BMPs are considered one of the major groups
of morphogenetic factors that mediate pat-
terning and growth of many tissue types
during embryogenesis and organogenesis. In
the absence of specifi c BMPs, certain systems
fail to develop, resulting in embryonic defects
is primarily expressed in the endoderm of
mouse pregastrula and gastrula embryos and
that the PGC generation in the mouse embryo
is regulated not only by extraembryonic ecto-
derm-derived BMP-
4
and BMP-
8
B, but also by
endoderm-derived BMP-
2
[
223
].
has been extensively studied. It is
expressed later during mammalian develop-
BMP-
7
