Biomedical subjects

Jonathan R Terman

Publications and source records attributed to Jonathan R Terman.

7 recordsLinked to original sources

PubMed2006

Drosophila Plexin B is a Sema-2a receptor required for axon guidance.

Plexin receptors play a crucial role in the transduction of axonal guidance events elicited by semaphorin proteins. In Drosophila, Plexin A (PlexA) is a receptor for the transmembrane semaphorin semaphorin-1a (Sema-1a) and is required for motor and central nervous system (CNS) axon guidance in the developing embryonic nervous system. However, it remains unknown how PlexB functions during neural development and which ligands serve to activate this receptor. Here, we show that plexB, like plexA, is robustly expressed in the developing CNS and is required for motor and CNS axon pathfinding. PlexB and PlexA serve both distinct and shared neuronal guidance functions. We observe a physical association between these two plexin receptors in vivo and find that they can utilize common downstream signaling mechanisms. PlexB does not directly bind to the cytosolic semaphorin signaling component MICAL (molecule that interacts with CasL), but requires MICAL for certain axonal guidance functions. Ligand binding and genetic analyses demonstrate that PlexB is a receptor for the secreted semaphorin Sema-2a, suggesting that secreted and transmembrane semaphorins in Drosophila use PlexB and PlexA, respectively, for axon pathfinding during neural development. These results establish roles for PlexB in central and peripheral axon pathfinding, define a functional ligand for PlexB, and implicate common signaling events in plexin-mediated axonal guidance.

Animals↗

PubMed2006

The semaphorins.

Semaphorins are secreted, transmembrane, and GPI-linked proteins, defined by cysteine-rich semaphorin protein domains, that have important roles in a variety of tissues. Humans have 20 semaphorins, Drosophila has five, and two are known from DNA viruses; semaphorins are also found in nematodes and crustaceans but not in non-animals. They are grouped into eight classes on the basis of phylogenetic tree analyses and the presence of additional protein motifs. The expression of semaphorins has been described most fully in the nervous system, but they are also present in most, or perhaps all, other tissues. Functionally, semaphorins were initially characterized for their importance in the development of the nervous system and in axonal guidance. More recently, they have been found to be important for the formation and functioning of the cardiovascular, endocrine, gastrointestinal, hepatic, immune, musculoskeletal, renal, reproductive, and respiratory systems. A common theme in the mechanisms of semaphorin function is that they alter the cytoskeleton and the organization of actin filaments and the microtubule network. These effects occur primarily through binding of semaphorins to their receptors, although transmembrane semaphorins also serve as receptors themselves. The best characterized receptors for mediating semaphorin signaling are members of the neuropilin and plexin families of transmembrane proteins. Plexins, in particular, are thought to control many of the functional effects of semaphorins; the molecular mechanisms of semaphorin signaling are still poorly understood, however. Given the importance of semaphorins in a wide range of functions, including neural connectivity, angiogenesis, immunoregulation, and cancer, much remains to be learned about these proteins and their roles in pathology and human disease.

Animals↗

PubMed2005

High-resolution structure of the catalytic region of MICAL (molecule interacting with CasL), a multidomain flavoenzyme-signaling molecule.

Semaphorins are extracellular cell guidance cues that govern cytoskeletal dynamics during neuronal and vascular development. MICAL (molecule interacting with CasL) is a multidomain cytosolic protein with a putative flavoprotein monooxygenase (MO) region required for semaphorin-plexin repulsive axon guidance. Here, we report the 1.45-A resolution crystal structure of the FAD-containing MO domain of mouse MICAL-1 (residues 1-489). The topology most closely resembles that of the NADPH-dependent flavoenzyme p-hydroxybenzoate hydroxylase (PHBH). Comparison of structures before and after reaction with NADPH reveals that, as in PHBH, the flavin ring can switch between two discrete positions. In contrast with other MOs, this conformational switch is coupled with the opening of a channel to the active site, suggestive of a protein substrate. In support of this hypothesis, distinctive structural features highlight putative protein-binding sites in suitable proximity to the active site entrance. The unusual juxtaposition of this N-terminal MO (hydroxylase) activity with the characteristics of a multiprotein-binding scaffold exhibited by the C-terminal portion of the MICALs represents a unique combination of functionality to mediate signaling.

Animals↗

PubMed2005

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

MICALs comprise of a family of phylogenetically conserved, multidomain cytosolic flavoprotein monooxygenases. Drosophila (D-)MICAL binds the neuronal Sema1a receptor PlexA, and D-MICAL-PlexA interactions are required in vivo for Sema1a-induced axon repulsion. The biological functions of vertebrate MICAL proteins, however, remain unknown. Here, we describe three rodent MICAL genes and analyze their expression in the intact rat nervous system and in two models of spinal cord injury. MICAL-1, -2, and -3 expression patterns in the embryonic, postnatal, and adult nervous system support the idea that MICALs play roles in neural development and plasticity. In addition, MICAL expression is elevated in oligodendrocytes and in meningeal fibroblasts at sites of spinal cord injury but is unchanged in lesioned corticospinal tract neurons. Furthermore, we find that the selective monooxygenase inhibitor EGCG attenuates the repulsive effects of Sema3A and Sema3F in vitro, but not those of several other repulsive cues and substrates. These results implicate MICALs in neuronal regeneration and support the possibility of employing EGCG to attenuate Sema3-mediated axon repulsion in the injured spinal cord.

Animals↗

PubMed2004

The Drosophila receptor guanylyl cyclase Gyc76C is required for semaphorin-1a-plexin A-mediated axonal repulsion.

Cyclic nucleotide levels within extending growth cones influence how navigating axons respond to guidance cues. Pharmacological alteration of cAMP or cGMP signaling in vitro dramatically modulates how growth cones respond to attractants and repellents, although how these second messengers function in the context of guidance cue signaling cascades in vivo is poorly understood. We report here that the Drosophila receptor-type guanylyl cyclase Gyc76C is required for semaphorin-1a (Sema-1a)-plexin A repulsive axon guidance of motor axons in vivo. Our genetic analyses define a neuronal requirement for Gyc76C in axonal repulsion. Additionally, we find that the integrity of the Gyc76C catalytic cyclase domain is critical for Gyc76C function in Sema-1a axon repulsion. Our results support a model in which cGMP production by Gyc76C facilitates Sema-1a-plexin A-mediated defasciculation of motor axons, allowing for the generation of neuromuscular connectivity in the developing Drosophila embryo.

Amino Acid Sequence↗

PubMed2004

Nervy links protein kinase a to plexin-mediated semaphorin repulsion.

Cyclic nucleotides regulate axonal responses to a number of guidance cues through unknown molecular events. We report here that Drosophila nervy, a member of the myeloid translocation gene family of A kinase anchoring proteins (AKAPs), regulates repulsive axon guidance by linking the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) to the Semaphorin 1a (Sema-1a) receptor Plexin A (PlexA). Nervy and PKA antagonize Sema-1a-PlexA-mediated repulsion, and the AKAP binding region of Nervy is critical for this effect. Thus, Nervy couples cAMP-PKA signaling to PlexA to regulate Sema-1a-mediated axonal repulsion, revealing a simple molecular mechanism that allows growing axons to integrate inputs from multiple guidance cues.

Adaptor Proteins, Signal Transducing↗

PubMed2002

MICALs, a family of conserved flavoprotein oxidoreductases, function in plexin-mediated axonal repulsion.

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.

Actins↗