Balancing act

Early in development, embryos transition from being simple spheres of cells into more structured forms in which the foundations of body patterning—such as distinct dorsal (back) and ventral (front) sides—have been established.

Dorsal–ventral patterning is primarily established by BMP signaling factors, which exhibit a gradient of activity along the length of the embryo: elevated BMP activity induces ventral development, while reduced BMP signaling induces dorsality. Reduction in BMP activity is mediated by a structure known as the Spemann organizer, which secretes factors like Chordin, which inactivates BMP and drives dorsalization.

However, BMP also represses Chordin expression, creating a seemingly fragile regulatory situation in which transient upregulation of Chordin could trigger a chain reaction of uncontrolled Chordin upregulation, with catastrophic results for body patterning.

This isn’t the case; in fact, this process is surprisingly robust. Yoshiki Sasai of the RIKEN Center for Developmental Biology in Kobe, suspected that additional failsafe mechanisms must exist to stabilize Chordin–BMP regulation, and decided to investigate the involvement of a protein recently discovered by his team, ONT1, which they thought might play a role in body patterning (1).

ONT1 is produced and secreted by cells in the dorsal region of the embryo, where it appears to directly regulate Chordin function, and Sasai’s team found that frog embryos with reduced ONT1 activity are far more vulnerable to excessive dorsalization in the presence of abnormally elevated Chordin levels. “We were really surprised to see how drastically the stability collapsed after knocking down ONT1 function,” he says.

They determined that ONT1 not only interacts directly with Chordin, but also binds to an enzyme known to degrade Chordin, and came to the surprising conclusion that ONT1 acts as a bridge that links the two proteins and thereby expedites destruction of the dorsalization signal. “There are a number of examples of intracellular scaffolds,” says Sasai, “but ONT1 is a rare example of a secreted scaffold for enzymes.”

There is another recently identified pathway for the regulation of dorsal–ventral patterning, mediated by ADMP, a protein that reduces Chordin levels by activating BMP receptors, and ONT1 and ADMP appear to regulate parallel but independent pathways for ensuring robust control of dorsalization in the embryo.

The researchers now hope to delve deeper into this more complex model of organizer regulation. “One important approach will be to establish a mathematical model for this integrated view of organizer function,” says Sasai, “particularly to explain these phenomena in a spatial and real-time fashion.”

Reference

1. Inomata, H., Haraguchi, T. & Sasai, Y. Robust stability of the embryonic axial pattern requires a secreted scaffold for Chordin degradation. Cell 134, 854–865 (2008).

The corresponding author for this highlight is based at the RIKEN Laboratory for Organogenesis and Neurogenesis