Our ability to move is largely dependent on various classes of motor neurons in our spinal marrow that govern the control of our muscles from there. However, it has long been unknown just how this part of the central nervous system is formed during fetal development.

Edlund's research team has now identified the phase in which spinal marrow and motor neurons start to develop as well as the signal molecules that regulate this process. Taken together, the team's research has now elucidated how the various parts of the central nervous system are initially developed during the fetal period. The identification of the signal molecules and how they work has also made it possible to reprogram cells from the forebrain to form all other parts of the central nervous system, including motor neurons in spinal marrow.

The article, titled "An Early Role for Wnt Signaling in Specifying Neural Patterns of Cdx and Hox Gene Expression and Motor Neuron Subtype Identity," is published in the latest issue of the journal PloS Biology. Co-authors are doctoral candidates Ulrika Nordstrom and Esther Maier, both at UCMM.

umu.se

One new insight from the current study, for example, is that the point of contact between the two core domains of a pair of p53 proteins forming a dimer tracks to a part of the protein often mutated in cancers. This suggests that the interface between the two proteins of the dimer is likely as important for the proper functioning of the tetramer as its interface with DNA, which also depends on the interface of the core domains of the two p53 proteins that form a dimer.

In seeking to determine the structure of p53 bound to DNA, the challenge for the scientists was that their efforts to crystallize the p53 dimer bound to DNA consistently resulted in structures that could not bind to DNA. (Crystallization is a prerequisite for obtaining the type of three-dimensional image sought in this study.) The researchers found that the dimers formed in solution prior to crystallization attempts took on a form that was incompatible with DNA binding.

"There's an inactive form of the p53 dimer that's unable to bind DNA in the correct fashion," Marmorstein explains. "We knew there had to be a structural rearrangement of the core domains to allow p53 to bind DNA as a dimer. The core domain is what's binding the DNA, but within the dimer, the two cores have to be in the proper orientation to bind DNA.

"So we decided that we needed to somehow lock the protein into a conformation that's compatible with the dimer binding to DNA. We used a chemical trick in which we modified a DNA base to allow it to attach directly to a part of the protein's core domain. That allowed us to trap the form of the p53 dimer that's compatible with DNA binding. And we solved the structure. We saw what it looked like."

wistar