MICALs, a Family of Conserved Flavoprotein Oxidoreductases, Function in Plexin-Mediated Axonal Repulsion

Abstract

Members of the semaphorin family of secreted and transmembrane proteins utilize plexins as neuronal receptors to signal repulsive axon guidance. It remains unknown how plexin proteins are directly linked to the regulation of cytoskeletal dynamics. Here, we show that Drosophila MICAL, a large, multidomain, cytosolic protein expressed in axons, interacts with the neuronal plexin A (PlexA) receptor and is required for Semaphorin 1a (Sema-1a)-PlexA-mediated repulsive axon guidance. In addition to containing several domains known to interact with cytoskeletal components, MICAL has a flavoprotein monooxygenase domain, the integrity of which is required for Sema-1a-PlexA repulsive axon guidance. Vertebrate orthologs of Drosophila MICAL are neuronally expressed and also interact with vertebrate plexins, and monooxygenase inhibitors abrogate semaphorin-mediated axonal repulsion. These results suggest a novel role for oxidoreductases in repulsive neuronal guidance.

MICAL flavoprotein monooxygenases: Expression during neural development and following spinal cord injuries in the rat

“…In a search for plexin-interacting proteins in Drosophila, we identified Molecule interacting with CasL (MICAL; Suzuki et al, 2002) as a novel mediator of semaphorin signaling (Terman et al, 2002). MICALs comprise a small family of phylogenetically conserved cytosolic proteins that contain a putative NH 2 -terminal flavin-adenine dinucleotide (FAD)-binding monooxygenase domain.…”

“…MICALs comprise a small family of phylogenetically conserved cytosolic proteins that contain a putative NH 2 -terminal flavin-adenine dinucleotide (FAD)-binding monooxygenase domain. Drosophila (D-)MICAL binds the intracellular C2 region of the Sema1a receptor PlexA, and D-MICAL -PlexA interactions are required in vivo for Sema1a-induced motor axon repulsion in the developing Drosophila neuromuscular system (Terman et al, 2002). Site-directed mutagenesis leading to alterations in amino acids in the D-MICAL monooxygenase region likely to be essential for monooxygenase function attenuates repulsive Sema1a signaling in vivo (Terman et al, 2002).…”

“…Drosophila (D-)MICAL binds the intracellular C2 region of the Sema1a receptor PlexA, and D-MICAL -PlexA interactions are required in vivo for Sema1a-induced motor axon repulsion in the developing Drosophila neuromuscular system (Terman et al, 2002). Site-directed mutagenesis leading to alterations in amino acids in the D-MICAL monooxygenase region likely to be essential for monooxygenase function attenuates repulsive Sema1a signaling in vivo (Terman et al, 2002). In addition to D-MICAL, three human MICAL genes have been identified (MICAL-1, -2, and -3) (Suzuki et al, 2002;Terman et al, 2002;Weide et al, 2003).…”

“…Site-directed mutagenesis leading to alterations in amino acids in the D-MICAL monooxygenase region likely to be essential for monooxygenase function attenuates repulsive Sema1a signaling in vivo (Terman et al, 2002). In addition to D-MICAL, three human MICAL genes have been identified (MICAL-1, -2, and -3) (Suzuki et al, 2002;Terman et al, 2002;Weide et al, 2003). Expression analysis and yeast interaction experiments suggest that vertebrate MICALs function downstream of class 3 semaphorins (Sema3s) and their receptors, the vertebrate class A plexins (plexinAs) (Terman et al, 2002).…”

“…In addition to D-MICAL, three human MICAL genes have been identified (MICAL-1, -2, and -3) (Suzuki et al, 2002;Terman et al, 2002;Weide et al, 2003). Expression analysis and yeast interaction experiments suggest that vertebrate MICALs function downstream of class 3 semaphorins (Sema3s) and their receptors, the vertebrate class A plexins (plexinAs) (Terman et al, 2002). This idea gains support from the observation that certain green tea polyphenols which can specifically block flavoprotein monooxygenases, (À)-epigallocatechin gallate (EGCG) and (À)-epicatechin (EC) (Abe et al, 2000a,b), abrogate Sema3A-mediated repulsion of rat sensory axons in vitro (Terman et al, 2002).…”