.
The various bone morphogenetic protein (BMP) signaling factors play an important role in early neural
development in the vertebrate embryo. However, maturation of these tissues ultimately depends on the
coordinated activity of factors that suppress BMP activity within the neuroectoderm, a cell population that
ultimately gives rise to the nervous system.
.
Yoshiki Sasai and colleagues at the RIKEN Center for Developmental Biology in Kobe have now revealed a
novel regulator of BMP signaling, Jiraiya1, which they originally identified in a screen for genes activated
by the BMP inhibitor Chordin in the African clawed frog, Xenopus laevis2. “Jiraiya was intriguing as it encoded
a novel membrane protein that had no homology to known proteins, and its expression was neural-specific,”
says Sasai.
.
Unexpectedly, his team determined that the Jiraiya protein acts as a specific inhibitor of BMPRII, one of two
core subunits of the BMP receptor, within the neuroectoderm (Fig. 1). BMPRII chemically modifies BMPRI in
response to BMP binding; BMPRI subsequently activates downstream components of the signaling cascade.
Initial experiments showed that Jiraiya specifically interferes with signaling at a point between ligand binding
and BMPRI activation.
.
.
Figure 1: Staining reveals the specific expression of the Jiraiya gene within the neuroectoderm of a
developing Xenopus embryo.
.
.
When overexpressed in cultured embryonic frog cells, Jiraiya depleted BMPRII from the plasma membrane by
sequestering it within complexes in the cytoplasm. Evidence suggests that this protein physically interferes
with the delivery of newly synthesized receptor molecules to the cell surface.
.
BMPRII is part of a larger family of receptor proteins that are relatively similar to one another, but features a
distinctive ‘C-terminal tail domain’ (TD) that contains within it the specific Jiraiya-binding motif. This enigmatic
‘EVNNNG’ sequence appears to be a unique feature of BMPRII, although it is closely conserved in receptor
homologues from other species. Transplantation of the motif onto a different receptor, ActRIIA, was sufficient
to make that protein susceptible to similar Jiraiya-mediated inhibition. “The most intriguing part is that it acts
only on the type II subunit of BMPR via this tail-domain whose role in dynamic signaling modulation had not
been known,” says Sasai.
.
He and his colleagues conclude that Jiraiya appears to represent an important mechanism for the cell-specific
inactivation of BMP-responsive pathways, and thereby helps define the boundaries of neural tissue development.
The Jiraiya gene is found in a broad range of vertebrate species, although expression in the mouse embryo
does not seem to follow the same neural-specific pattern of localization seen in frog embryos. Sasai hopes to
further clarify its role in mammalian development in future studies.
.
