Novel signaling molecules in the brain

Axonal guidance cues generally regulate proteins such as RhoA, which direct the remodeling of cytoskeleton, thereby promoting axonal turning and axonal growth.  However, recently it was found that MICAL, an enzyme that has homology to isoprenoid lipid-synthesizing enzymes, is required for axonal guidance in response to Semaphorin 3A.  This was a particularly intriguing since it suggested that novel models of signaling are utilized for axon guidance.

One possibility is that Semaphorin 3A regulates MICAL, resulting in the prodction of a signaling molecule.  Despite its homology to lipid-synthesizing enzymes, it is currently unknown if MICAL also synthesizes lipids or potentially other small molecules.  We are currently using a metabolomic approach to identify potential products of MICAL activity.  These experiments could result in the identification of novel signaling molecules in axons which could potentially have effects in a wide variety of cells.

Another possibility is that MICAL does not synthesize a traditional signaling molecule.  Indeed, MICAL has been found to generate unusually large amounts of hydrogen peroxide, and it has been proposed that the MICAL dependence in Semaphorin 3A signaling may reflect a role for hydrogen peroxide in axon guidance.  Since hydrogen peroxide can modify proteins at cysteine residues, MICAL might regulate protein function by modifying cysteine residues in specific target proteins.  Using novel proteomic approaches, we are discovering proteins that are selectively modified by MICAL activity.

Importantly, MICAL is expressed in nearly all cell types, suggesting that MICAL signaling has widespread roles in many aspects of biology, not just axon guidance.  Studying MICAL signaling in axons will allow provide insight into the general function of MICAL in cells, and will have importance for numerous biological processes.