Semaphorin 7A promotes axon outgrowth through integrins and MAPKs

Abstract

Striking parallels exist between immune and nervous system cellular signalling mechanisms. Molecules originally shown to be critical for immune responses also serve neuronal functions, and similarly neural guidance cues can modulate immune function. We show here 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. Unlike many other semaphorins, which act as repulsive guidance cues, Sema7A enhances central and peripheral axon growth and is required for proper axon tract formation during embryonic development. Unexpectedly, Sema7A enhancement of axon outgrowth requires integrin receptors and activation of MAPK signalling pathways. These findings define a previously unknown biological function for semaphorins, identify an unexpected role for integrins and integrin-dependent intracellular signalling in mediating semaphorin responses, and provide a framework for understanding and interfering with Sema7A function in both immune and nervous systems.

Cocaine-induced expression changes of axon guidance molecules in the adult rat brain

“…Sema6C, which is strongly down regulated in all brain regions and in all conditions, is highly expressed in the lateral ventricle, the striatum, the midbrain, the pons/midbrain junction, and the choroid plexus (Qu et al, 2002). Finally, Sema7A, a glycosylphosphatidylinositol-linked semaphorin strongly downregulated in the Ventral Tegmental Area after drug treatment, displays highest expression in the nervous system and in the adult brain (Sato and Takahashi, 1998, Xu et al, 1998, Lange et al, 1998 and promotes axon growth through integrin receptors (Pasterkamp et al, 2003). From our study, one is surprised that such a large variety of semaphorins and related receptors display expression changes after drug treatment.…”

Poxvirus semaphorin A39R inhibits phagocytosis by dendritic cells and neutrophils

“…OT-I mice are specific for chicken OVA peptide 257-264 (SIINFEKL) in the context of H-2K b . The generation of plexin C1 -/-mice has been described [25]. plexin C1 -/-mice were bred in house.…”

Regulation of immune cell responses by semaphorins and their receptors

“…For example, Sema3E signals independently of NPs through plexin-D1, 16 while Sema7A uses integrins to exert its functions in both the nervous and immune systems. 27,28 In addition, two molecules unrelated to plexins and NPs, CD72 29 and T-cell immunoglobulin and mucin domaincontaining protein 2 (TIM-2), 30 functionally interact with Sema4D and Sema4A, respectively, in the immune system (Figure 1).…”

“…27 Sema7A contains an arginine-glycineaspartate in its Sema domain that is a well-conserved integrin-binding motif. 28 Recombinant Sema7A protein stimulates monocytes/macrophages through a1b1 integrin, inducing proinflammatory cytokine production. 27 Furthermore, Sema7A receptor usage in the immune system is consistent with that in olfactory nerve outgrowth.…”

“…27 Furthermore, Sema7A receptor usage in the immune system is consistent with that in olfactory nerve outgrowth. 28 Sema7A is also involved in pathogenic immune responses. Sema7A-deficient mice are resistant to inflammation, including hapten-induced contact hypersensitivity and EAE.…”