Semaphorins Play Regulatory Role in Nervous System Development

Researchers looking at the similarities between the immune system and the nervous system have found that semaphorin 7A (Sema7A), a membrane-anchored member of the semaphorin family of guidance proteins previously known for its immunomodulatory effects, can also mediate neuronal functions.

Semaphorins are a family of proteins that mediate neuronal guidance by inhibiting nerve-growth cone movement. Both transmembrane and secreted proteins are included, and many domains of the proteins are highly conserved between invertebrates and vertebrates. Most are around 750 residues with a conserved "sema” domain of up to 500 extracellular residues with a single immunoglobulin C2-type domain C-terminal.

The investigators, from Johns Hopkins University (Baltimore, MD, USA), showed that unlike many other semaphorins, which act as repulsive guidance cues, Sema7A enhanced central and peripheral axon growth and was required for proper axon tract formation during embryonic development. Sema7A enhancement of axon outgrowth required integrin receptors and activation of MAPK signaling pathways.

These findings, published in the July 24, 2003, issue of Nature, define a previously unknown biological function for semaphorins. They identify an unexpected role for integrins and integrin-dependent intracellular signaling in mediating semaphorin responses and provide a framework for understanding and interfering with Sema7A function in both immune and nervous systems.

"I have been studying semaphorins for about a decade and did not expect to find any that stimulated axon growth, certainly not to the extent we saw in the lab and in mice,” said senior author Dr. Alex Kolodkin, professor of neuroscience at Johns Hopkins University. "Now we need to figure out how semaphorins balance their repulsive and attractive effects.”




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