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Edward De Robertis (right) and Bruno Reversade
De Robertis and Reversade, both at University of California, Los Angeles, sought to understand the possible role of the regulatory molecules called bone morphogenetic proteins (BMPs). Other studies have shown BMPs to be key regulators in the dorsoventral (back-to-belly) patterning of embryos whereby dorsal cells differentiate into neural cells, and ventral cells become epidermal cells. Yet, no one had been able to demonstrate their role by shutting down the system and eliminating such embryonic "self-regulation."
In their experiments with embryos of the African frog Xenopus, the researchers split the embryos into dorsal and ventral halves and used sophisticated molecular techniques to selectively inhibit BMP signaling in each half. They then observed the effects of their manipulations on embryonic development.
The experiments, published in the December 16, 2005, issue of Cell, revealed that while the ventral half of the embryo requires specific BMPs for normal development, "it was rather shocking to us that the dorsal part of the embryo developed fairly normally," says De Robertis. Indeed, further experiments revealed that normal dorsal development instead requires a different member of the BMP family, called anti-dorsalizing morphogenetic protein (ADMP).
Importantly, De Robertis and Reversade discovered that the two kinds of proteins in embryo halves are regulated in a seesaw fashion. When the researchers decreased BMP signaling levels, they found that ADMP levels would rise, and vice versa. This compensatory ability is a key to self-regulation in the embryo, according to De Robertis.
Another surprise came when the researchers shut down all the relevant BMP proteins, including ADMP, in Xenopus embryos. The entire surface of the embryo became neural tissue. "This is a major transformation of a type you almost never see in embryos," says De Robertis. "It told us that BMPs play a crucial role in the establishment of a self-regulating morphogenetic field for dorsoventral patterning." In fact, when the scientists grafted material from either dorsal or ventral BMP sources into embryos depleted of all BMPs, either of the grafts could restore normal embryo formation.
"We think this finding is important in showing that the embryo is probably patterned by two gradients of BMP—one from the dorsal side and one from the ventral," says De Robertis. "The key to making a perfect baby every time, these experiments tell us, lies in the ability to have a double gradient that will ensure a robust developmental system."
This discovery could also have important implications for efforts to use stem cells to rejuvenate tissues lost to disease or trauma. When cultured in vitro, stem cells tend to differentiate into multiple cell types, as their self-regulatory systems work to produce an embryo. De Robertis suggests it might be necessary to shut down such self-regulation in stem cells to induce them to produce specific tissues.
Photo: Hiroki Kuroda