The role of semaphorins in immune responses and autoimmune rheumatic diseases.

Semaphorins have a well-characterized role in guiding axon repulsion during development; however, the important contribution of these proteins in immunity is becoming increasingly clear. Immunoregulatory semaphorins, termed 'immune semaphorins', have roles in regulating immune cell activation, differentiation, mobility and migration. These proteins are also intimately associated with the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This Review discusses the pathogenic functions of immune semaphorins, as well as the potential use of these molecules as diagnostic markers and therapeutic targets for the treatment of autoimmune diseases.

Netrins & Semaphorins: Novel regulators of the immune response.

Netrins and semaphorins, members of the neuronal guidance cue family, exhibit a rich biology with significant roles that extend beyond chemotactic guidance of the axons to build the neuronal patterns of the body. Screening of adult tissues and specific cellular subsets have illuminated that these proteins are also abundantly expressed under both steady state and pathological scenarios. This observation suggests that, in addition to their role in the development of the axonal tree, these proteins possess additional novel functions in adult physiopathology. Notably, a series of striking evidence has emerged in the literature describing their roles as potent regulators of both innate and adaptive immunity, providing extra dimension to our knowledge of neuronal guidance cues. In this review, we summarize the key complex roles of netrins and semaphorins outside the central nervous system (CNS) with focus on their immunomodulatory functions that impact pathophysiological conditions.

The semaphorins and their receptors as modulators of tumor progression.

The semaphorins were initially characterized as repulsive axon guidance factors. However, they are currently also recognized as important regulators of diverse biological processes which include regulation of immune responses, angiogenesis, organogenesis, and a variety of additional physiological and developmental functions. The semaphorin family consists of more than 20 genes divided into seven subfamilies, all of which contain the sema domain signature. They usually transduce signals by activation of receptors belonging to the plexin family, either directly, or indirectly following the binding of some semaphorins to receptors of the neuropilin family which subsequently associate with plexins. Additional receptors which form complexes with these primary semaphorin receptors are also frequently involved in semaphorin signalling, and can strongly influence the nature of the biological responses of cells to semaphorins. Recent evidence suggests that semaphorins play important roles in the etiology of multiple forms of cancer. Some semaphorins such as some semaphorins belonging to the class-3 semaphorin subfamily, have been found to function as bona fide tumor suppressors and to inhibit tumor progression by various mechanisms. Because these class-3 semaphorins are secreted proteins, these semaphorins may potentially be used as anti-tumorigenic drugs. Other semaphorins, such as semaphorin-4D, function as inducers of tumor progression and represent targets for the development of novel anti-tumorigenic drugs. The mechanisms by which semaphorins affect tumor progression are diverse, ranging from direct effects on tumor cells to modulation of accessory processes such as modulation of immune responses and inhibition or promotion of tumor angiogenesis and tumor lymphangiogenesis. This review focuses on the diverse mechanisms by which semaphorins affect tumor progression.

A combinatorial semaphorin code instructs the initial steps of sensory circuit assembly in the Drosophila CNS.

Longitudinal axon fascicles within the Drosophila embryonic CNS provide connections between body segments and are required for coordinated neural signaling along the anterior-posterior axis. We show here that establishment of select CNS longitudinal tracts and formation of precise mechanosensory afferent innervation to the same CNS region are coordinately regulated by the secreted semaphorins Sema-2a and Sema-2b. Both Sema-2a and Sema-2b utilize the same neuronal receptor, plexin B (PlexB), but serve distinct guidance functions. Localized Sema-2b attraction promotes the initial assembly of a subset of CNS longitudinal projections and subsequent targeting of chordotonal sensory afferent axons to these same longitudinal connectives, whereas broader Sema-2a repulsion serves to prevent aberrant innervation. In the absence of Sema-2b or PlexB, chordotonal afferent connectivity within the CNS is severely disrupted, resulting in specific larval behavioral deficits. These results reveal that distinct semaphorin-mediated guidance functions converge at PlexB and are critical for functional neural circuit assembly.

Semaphorins and their receptors in lung cancer.

Semaphorins are a large family of secreted, transmembrane and GPI-linked proteins initially characterized in the development of the nervous system and axonal guidance. Semaphorins are expressed in many tissues where they regulate normal development, organ morphogenesis, immunity and angiogenesis. They affect the cytoskeleton, actin filament organization, microtubules and cell adhesion. Semaphorin signaling is transduced by plexins, which in the case of most class-3 semaphorins requires high-affinity neuropilin receptors. The neuropilins also function as receptors for VEGF and other growth factors, and their expression is often abnormal in tumors. In cancer, semaphorins have both tumor suppressor and tumor promoting functions. We review here the current status of semaphorins and their receptors in tumor development with a focus on lung cancer.

Immune semaphorins: novel features of neural guidance molecules.

INTRODUCTION: The immune and nervous system have various common features in the functional characteristics. Both have an intricate network of synaptic connections and an exquisite communication system that enables intercellular signal transduction. They also share a number of messenger molecules such as cytokines and chemical mediators. DISCUSSION: Semaphorins, well-defined axonal guidance molecules in the nervous system, also play critical roles in immune regulation. Various types of semaphorins, including secreted, transmembrane, truncated, and glycosylphosphatidylinositol-anchored forms, function during immune responses. However, some semaphorins utilize receptors in the immune system that are distinct from receptors in the nervous system. CONCLUSION: This review presents a current overview of 'immune semaphorins' and their receptors, providing insight into the pleiotropic activity of this protein family.

Signaling of secreted semaphorins in growth cone steering.

Despite a tremendous amount of progress in the identification and characterization of many new players as components of class 3 secreted semaphorin signaling in growth cone steering (Fig. 1), our understanding of the molecular mechanisms is far from complete. More questions remain to be answered: how are differential cytoskeletal changes within a growth cone achieved in response to semaphorins? What are the target(s) of cyclic nucleotide modulation? How does a growth cone make a reliable decision in response to a shallow gradient? And finally, how does a growth cone maintain its sensitivity to a decreasing concentration ofsemaphorins when it is growing away from the source? With a high degree of interest in the field with the development of novel technologies in analyzing growth cone steering, we expect to see a much more complete picture of semaphoring signaling in the near future.

Semaphorin signaling in vascular and tumor biology.

The neuropilins were originally characterized as cell membrane receptors that bind axon guidance factors belonging to the class-3 semaphorin subfamily. To transduce semaphorin signals, they form complexes with members of the plexin receptor family in which neuropilins serve as the ligand binding components and the plexins as the signal transducing components. The neuropilins were subsequently found to double as receptors for specific heparin binding splice forms of vascular endothelial growth factor (VEGF), and to be expressed on endothelial cells. This finding suggested that semaphorins may function as modulators of angiogenesis. It was recently found that several types of semaphorins such as semaphorin-3F function as inhibitors of angiogenesis while others, most notably semaphorin-4D, function as angiogenic factors. Furthermore, semaphorins such as semaphorin-3F and semaphorin-3B have been characterized as tumor suppressors and have been found to exert direct effects upon tumor cells. In this chapter we cover recent developments in this rapidly developing field of research.

An RNAi-based approach identifies molecules required for glutamatergic and GABAergic synapse development.

We report the results of a genetic screen to identify molecules important for synapse formation and/or maintenance. siRNAs were used to decrease the expression of candidate genes in neurons, and synapse development was assessed. We surveyed 22 cadherin family members and demonstrated distinct roles for cadherin-11 and cadherin-13 in synapse development. Our screen also revealed roles for the class 4 Semaphorins Sema4B and Sema4D in the development of glutamatergic and/or GABAergic synapses. We found that Sema4D affects the formation of GABAergic, but not glutamatergic, synapses. Our screen also identified the activity-regulated small GTPase Rem2 as a regulator of synapse development. A known calcium channel modulator, Rem2 may function as part of a homeostatic mechanism that controls synapse number. These experiments establish the feasibility of RNAi screens to characterize the mechanisms that control mammalian neuronal development and to identify components of the genetic program that regulate synapse formation and/or maintenance.

A semaphorin code defines subpopulations of spinal motor neurons during mouse development.

Abstract In the spinal cord, motor neurons (MNs) with similar muscle targets and sensory inputs are grouped together into motor pools. To date, relatively little is known about the molecular mechanisms that control the establishment of pool-specific circuitry. Semaphorins, a large family of secreted and cell surface proteins, are important mediators of developmental processes such as axon guidance and cell migration. Here, we used mRNA in situ hybridization to study the expression patterns of semaphorins and their receptors, neuropilins and plexins, in the embryonic mouse spinal cord. Our data show that semaphorins and their receptors are differentially expressed in MNs that lie in distinct locations within the spinal cord. Furthermore, we report a combinatorial expression of class 3 (secreted) semaphorins and their receptors that characterizes distinct motor pools within the brachial and lumbar spinal cord. Finally, we found that a secreted semaphorin, Sema3A, elicits differential collapse responses in topologically distinct subpopulations of spinal MNs. These findings lead us to propose that semaphorins and their receptors might play important roles in the sorting of motor pools and the patterning of their afferent and efferent projections.