Semaphorin4A causes loss of mature oligodendrocytes and demyelination in vivo.

BACKGROUND: Inappropriate contact between the immune system and the central nervous system is thought to be a cause of demyelination. We previously reported the ability of the class IV semaphorin, Semaphorin4A (Sema4A), to induce apoptosis in human oligodendrocytes; however, these results have yet to be translated to an in vivo setting. Importantly, HIV-associated neurocognitive disorder remains a significant complication for patients on combined anti-retroviral therapy, with white matter damage seen on MRI. METHODS: Human cerebrospinal fluid and serum was assayed for Sema4A using a Sema4A-specific ELISA. Wild-type mice were injected with Sema4A via stereotaxic infusion. Data was assessed for significance using unpaired t tests, comparing the corpus callosum of PBS-injected mice versus Sema4A-injected mice. RESULTS: Here, we demonstrate elevated levels of Sema4A in the cerebrospinal fluid and serum of people with HIV infection. Furthermore, we demonstrate that direct injection of Sema4A into the corpus callosum of mice results in loss of myelin architecture and decreased myelin, concomitant with apoptosis of mature myelinating oligodendrocytes. Sema4A injection also causes increased activation of microglia. CONCLUSIONS: Taken together, our data further establish Sema4A as a potentially significant mediator of demyelinating diseases and a direct connection between the immune system and oligodendrocytes.

Semaphorin4A and H-ferritin utilize Tim-1 on human oligodendrocytes: A novel neuro-immune axis.

Deficiency of trophic factors relating to the survival of oligodendrocytes, combined with direct interactions with the immune system, are favored paradigms that are increasingly implicated in demyelinating diseases of the central nervous system. We and others have previously shown that Sema4A and H-ferritin interact through the T-cell immunoglobulin and mucin domain (Tim-2) receptor in mice. H-ferritin has been identified as the iron delivery protein for oligodendrocytes, whereas Sema4A causes a direct cytotoxic effect. However, the expression of Tim-2 has not been detected in humans. Here, we demonstrate that, similar to rodents, human oligodendrocytes undergo apoptosis when exposed to Sema4A and take up H-ferritin for meeting iron requirements and that these functions are mediated via the Tim-1 receptor. Moreover, we also demonstrate the ability of H-ferritin to block Sema4A-mediated cytotoxicity. Furthermore, we show in a series of pilot studies that Sema4A is detectable in the CSF of multiple sclerosis patients and HIV-seropositive persons and can induce oligodendrocyte cell death. Together, these results identify a novel iron uptake mechanism for human oligodendrocytes and a connection between oligodendrocytes and the immune system.

Semaphorin 7a exerts pleiotropic effects to promote breast tumor progression.

Understanding what drives breast tumor progression is of utmost importance for blocking tumor metastasis; we have identified that semaphorin 7a is a potent driver of ductal carcinoma in situ (DCIS) progression. Semaphorin 7a is a glycophosphatidylinositol membrane-anchored protein that promotes attachment and spreading in multiple cell types. Here, we show that increased expression of SEMA7A occurs in a large percentage of breast cancers and is associated with decreased overall and distant metastasis-free survival. In both in vitro and in vivo models, short hairpin-mediated silencing of SEMA7A reveals roles for semaphorin 7a in the promotion of DCIS growth, motility and invasion as well as lymphangiogenesis in the tumor microenvironment. Our studies also uncover a relationship between COX-2 and semaphorin 7a expression and suggest that semaphorin 7a promotes tumor cell invasion on collagen and lymphangiogenesis via activation of ß1-integrin receptor. Our results suggest that semaphorin 7a may be novel target for blocking breast tumor progression.

The role of Sema4D/CD100 as a therapeutic target for tumor microenvironments and for autoimmune, neuroimmune and bone diseases.

INTRODUCTION: Semaphorin 4D (Sema4D), also known as CD100, has been implicated in physiologic roles in the immune and nervous systems. However, the interaction of Sema4D with its high affinity receptor, Plexin-B1, reveals a novel role for Sema4D produced by the tumor microenvironment in tumor angiogenesis and metastasis. AREAS COVERED: The ligation of Sema4D/CD100 with CD72 on immune and inflammatory cells is known to stimulate immune responses and regulation. Because CD100 and CD72 are expressed on lung immune and nonimmune cells, as well as on mast cells, the CD100/CD72 interaction plays another important role in allergic airway inflammation and mast cell functions. A better understanding of Sema4D-mediated cell signaling in physiological and pathological processes may be crucial for crafting new Sema4D-based therapeutics for human disease and tumor microenvironments. Strategies to achieve effective management through treatment with Sema4D include special siRNAs, neutralizing antibodies and knockdown. EXPERT OPINION: This review focuses on the links between Sema4D and human diseases such as cancer, bone metabolism, immune responses and organ development. The current knowledge regarding the expression of Sema4D and its receptors and its functional roles is systemically reviewed to explore Sema4D as both a target and a therapeutic in human diseases.

Semaphorin7A regulates neuroglial plasticity in the adult hypothalamic median eminence.

Reproductive competence in mammals depends on the projection of gonadotropin-releasing hormone (GnRH) neurons to the hypothalamic median eminence (ME) and the timely release of GnRH into the hypothalamic-pituitary-gonadal axis. In adult rodents, GnRH neurons and the specialized glial cells named tanycytes periodically undergo cytoskeletal plasticity. However, the mechanisms that regulate this plasticity are still largely unknown. We demonstrate that Semaphorin7A, expressed by tanycytes, plays a dual role, inducing the retraction of GnRH terminals and promoting their ensheathment by tanycytic end feet via the receptors PlexinC1 and Itgb1, respectively. Moreover, Semaphorin7A expression is regulated during the oestrous cycle by the fluctuating levels of gonadal steroids. Genetic invalidation of Semaphorin7A receptors in mice induces neuronal and glial rearrangements in the ME and abolishes normal oestrous cyclicity and fertility. These results show a role for Semaphorin7A signalling in mediating periodic neuroglial remodelling in the adult ME during the ovarian cycle.