Time-Dependent Molecular Switch Controls Axon-Spreading in the Developing Brain

They reported in the November 21, 2012, online edition of the journal Neuron that the protein Sonic Hedgehog (Shh) attracted axons in the developing spinal cord ventrally toward the floorplate. However, after crossing the floorplate, these axons switched their response to Shh from attraction to repulsion, so that they were repelled anteriorly by a posterior-high/anterior-low Shh gradient along the longitudinal axis.

The activity of Shh was found to be controlled by a group of proteins known as 14-3-3. These proteins comprise a family of conserved regulatory molecules expressed in all eukaryotic cells. The name 14-3-3 refers to the particular elution and migration pattern of these proteins on DEAE-cellulose chromatography and starch-gel electrophoresis. The 14-3-3 proteins eluted in the 14th fraction of bovine brain homogenate and were found on positions 3.3 of subsequent electrophoresis. 14-3-3 proteins have the ability to bind a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and transmembrane receptors. More than 100 signaling proteins have been reported as 14-3-3 ligands.

The investigators showed that inhibition of 14-3-3 protein activity converted Shh-mediated repulsion of aged dissociated neurons to attraction and prevented the correct anterior turn. Conversely, overexpression of 14-3-3 proteins was sufficient to drive the switch from Shh-mediated attraction to repulsion both in vitro and in vivo.

“To properly form neural circuits, developing axons follow external signals to reach the right targets,” said senior author Dr. Frédéric Charron, professor of medicine at the Montreal Neurological Institute. “We discovered that nerve cells also have an internal clock, which changes their response to external signals as they develop over time.”

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Montreal Neurological Institute