2536.4.4 Molecular Interpretation of BMP Gradient Signaling
Accumulated data has provided insight into the mechanisms through which cells
interpret different BMP signaling levels to achieve different dorsoventral cell fates.
Typical models invoke a positional information mechanism, in which the graded
concentration of a morphogen determines cell fate. However, it is becoming clear
that there are spatiotemporal aspects to growth factor signaling gradients in general,
and to BMP gradients in particular. Recent experiments have shown that dorsalized
maternal-zygotic BMP receptor (acvr1) mutant fish (lost-a-fin) are rescued by
inducible acvr1 expression only if expression is initiated prior to the midgastrula
stage (Tucker et al. 2008 ). Similarly, inducible expression of chrd after the middle
of gastrulation fails to dorsalize wildtype embryos. Analogous results were seen in
Xenopus and in fish using timed application of an anti-BMPR drug (Wawersik et al.
2005 ; Kwon et al. 2010 ), further supporting the idea that early but not late exposure
to BMP signals is critical for inhibiting dorsal fates and promoting ventral fates.
Temporal regulation was particularly evident in timed Chrd induction experi-
ments. Dorsoanterior markers become progressively refractory to BMP inhibition,
whereas more lateral-posterior tissues (neural crest and pronephros) became pro-
gressively more sensitive (Tucker et al. 2008 ). These studies thus suggest that BMP
signaling is active later and longer in ventroposterior tissues and never active in
prospective organizer. Additionally, dorsoventral and anteroposterior patterning
occurred along a similar time course, indicating these processes are coordinated
(see also Sect. 6.5.2). Interestingly in these studies, embryos do not seem to sense
cumulative BMP exposure, as ventroposterior fates could still be induced with a late
burst of BMP signals (Tucker et al. 2008 ). As discussed above, the BMP gradient is
self- organizing, therefore a small pulse of BMP activity could potentially regener-
ate the activity gradient to regulate different cell fates. Threshold dose and temporal
aspects of exposure to BMP signals thus cooperate to specify axial patterning.
The nature of interpretation of the BMP gradient at the transcriptional level may
also partly underlie this temporally progressive dorsoventral patterning. In Xenopus
ectoderm cells, competence to respond to BMP is maintained throughout gastrula-
tion (Simeoni and Gurdon 2007 ). And transcription can be triggered rapidly and
requires the continuous receptor activation to maintain appropriate steady-state lev-
els of Smad1 in the nucleus (Simeoni and Gurdon 2007 ). These responses are dis-
tinct from those elicited during Activin/Tgfb-mediated mesoderm induction (Chap.
7 ), which are characterized by a more limited period of competence, extending
signaling from active endocytic complexes, delayed onset of transcription, and
cumulative sensing of ligand levels (Dyson and Gurdon 1998 ; Shimizu and Gurdon
1999 ; Bourillot et al. 2002 ; Piepenburg et al. 2004 ; Jullien and Gurdon 2005 ). The
molecular bases for the differences between Tgfb and BMP signaling, despite simi-
lar pathway architecture, is not known but may underlie the general tendency of
ventral signals to limit dorsal ones. These differences may also help explain the
temporal aspects of BMP responses, as discussed above, as well as the importance
of Smad1 as a center of signaling integration.
6 Vertebrate Axial Patterning: From Egg to Asymmetry