SEMA3F expression associates with survival in triple negative breast cancer.

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of semaphorin 3F, encoded by SEMA3F when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, SEMA3F expression was correlated with recurrence-free survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. SEMA3F may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

Semaphorin3F Drives Dendritic Spine Pruning through Rho-GTPase Signaling

Dendritic spines of cortical pyramidal neurons are initially overproduced then remodeled substantially in the adolescent brain to achieve appropriate excitatory balance in mature circuits. Here we investigated the molecular mechanism of developmental spine pruning by Semaphorin 3F (Sema3F) and its holoreceptor complex, which consists of immunoglobulin-class adhesion molecule NrCAM, Neuropilin-2 (Npn2), and PlexinA3 (PlexA3) signaling subunits. Structure-function studies of the NrCAM-Npn2 interface showed that NrCAM stabilizes binding between Npn2 and PlexA3 necessary for Sema3F-induced spine pruning. Using a mouse neuronal culture system, we identified a dual signaling pathway for Sema3F-induced pruning, which involves activation of Tiam1-Rac1-PAK1-3 -LIMK1/2-Cofilin1 and RhoA-ROCK1/2-Myosin II in dendritic spines. Inhibitors of actin remodeling impaired spine collapse in the cortical neurons. Elucidation of these pathways expands our understanding of critical events that sculpt neuronal networks and may provide insight into how interruptions to these pathways could lead to spine dysgenesis in diseases such as autism, bipolar disorder, and schizophrenia.

Genetically-Modified Macrophages Accelerate Myelin Repair

ABSTRACTDespite extensive progress in immunotherapies that reduce inflammation and relapse rate in patients with multiple sclerosis (MS), preventing disability progression associated with cumulative neuronal/axonal loss remains an unmet therapeutic need. Complementary approaches have established that remyelination prevents degeneration of demyelinated axons. While several pro-remyelinating molecules are undergoing preclinical/early clinical testing, targeting these to disseminated MS plaques is a challenge. In this context, we hypothesized that monocyte (blood) -derived macrophages may be used to efficiently deliver repair-promoting molecules to demyelinating lesions. Here, we used transplantation of genetically-modified hematopoietic stem cells (HSCs) to obtain circulating monocytes that overexpress Semaphorin 3F, a pro-remyelinating molecule. We show that Semaphorin 3F-expressing macrophages quickly infiltrate demyelinating spinal cord lesions, which increases oligodendrocyte progenitor cell recruitment and accelerates myelin repair. Our results provide a proof-of-concept that monocyte-derived macrophages could be used to deliver pro-remyelinating agents “at the right time and place”, suggesting novel means for remyelinating therapies in patients with MS.

Endothelial Semaphorin 3F Maintains Endothelial Barrier Function and Inhibits Monocyte Migration

In normal physiology, endothelial cells (ECs) form a vital barrier between the blood and underlying tissue controlling leukocyte diapedesis and vascular inflammation. Emerging data suggest that neuronal guidance cues, typically expressed during development, have roles outside the nervous system in vascular biology and immune responses. In particular, Class III semaphorins have been reported to affect EC migration and angiogenesis. While ECs express high levels of semaphorin 3F (SEMA3F), little is known about its function in mature ECs. Here we show that SEMA3F expression is reduced by inflammatory stimuli and increased by laminar flow. Endothelial cells exposed to laminar flow secrete SEMA3F, which subsequently binds to heparan sulfates on the surface of ECs. However, under pro-inflammatory conditions, reduced levels of SEMA3F make ECs more prone to monocyte diapedesis and display impaired barrier function as measured with an electric cell–substrate impedance sensing system and a microfluidic system. In addition, we demonstrate that SEMA3F can directly inhibit the migration of activated monocytes. Taken together, our data suggest an important homeostatic function for EC-expressed SEMA3F, serving as a mediator of endothelial quiescence.