Semaphorins and their transmembrane receptors, Plexins, are key regulators of axon guidance and development of neuronal connectivity. B-type Plexins respond to Class IV semaphorins and mediate a variety of developmental functions. Here we report that the expression of Plexin-B2 and its high-affinity ligand, Sema4C, persists in peripheral sensory neurons in adult life and is markedly increased in states of persistent pain in mice. Genetic deletion of Sema4C as well as adult-onset loss of Plexin-B2 leads to impairment of the development and duration of inflammatory hypersensitivity. Remarkably, unlike the neurodevelopmental functions of Plexin-B2 that solely rely on Ras signaling, we obtained genetic and pharmacological evidence for a requirement of RhoA-ROCK-dependent mechanisms as well as TRPA1 sensitization in pronociceptive functions of Sema4C-Plexin-B2 signaling in adult life. These results suggest important roles for Plexin-B2 signaling in sensory function that may be of therapeutic relevance in pathological pain.

Semaphorins and their receptors, plexins, are emerging as key regulators of various aspects of neural and nonneural development. Semaphorin 4D (Sema4D) and B-type plexins demonstrate distinct expression patterns over critical time windows during the development of the murine neocortex. Here, analysis of mice genetically lacking plexin-B1 or plexin-B2 revealed the significance of Sema4D-plexin-B signaling in cortical development. Deficiency of plexin-B2 resulted in abnormal cortical layering and defective migration and differentiation of several subtypes of cortical neurons, including Cajal-Retzius cells, GABAergic interneurons, and principal cells in vivo. In contrast, a lack of plexin-B1 did not impact on cortical development in vivo. In various ex vivo assays on embryonic forebrain, Sema4D enhanced the radial and tangential migration of developing neurons in a plexin-B2-dependent manner. These results suggest that Sema4D-plexin-B2 interactions regulate mechanisms underlying cell specification, differentiation, and migration during corticogenesis.Semaphorins were originally identified as a large family of axon guidance cues (13). Several recent studies have implicated them in distinct processes underlying the proliferation, differentiation, and migration of several cell types both inside and outside of the nervous system (13, 43). Cellular functions of semaphorins are mediated by cell surface receptors called plexins and their coreceptors called neuropilins (42). A large part of our current knowledge on the role of semaphorinplexin interactions in neural development stems from studies on plexin-A family proteins and their class III semaphorin ligands (13,21). In contrast, the role of B-type plexins and their ligands in the establishment of neural circuits is less well understood. Among the three B-type plexins, plexin-B1 and plexin-B2 are known to be expressed in neurons whereas plexin-B3 is expressed in oligodendrocytes (46). Semaphorin 4D (Sema4D), a class IV semaphorin which exists in a transmembrane form as well as a soluble protein, binds plexin-B1 with high affinity and plexin-B2 with low affinity (28, 42). In contrast, Sema4C has been reported to bind plexin-B2 with high affinity (12). Recently, we generated mice genetically lacking either plexin-B1 or plexin-B2 in a constitutive manner and observed a critical requirement for plexin-B signaling in neural tube closure and migration of cerebellar granule cell precursors (12). Although Sema4D, plexin-B1, and plexin-B2 are also highly expressed in the developing neocortex over embryonic stages (46), their functional roles in cortical development have not been characterized so far.Precise regulation of the cell cycle and temporal coordination of the characteristic programs governing cell migration and differentiation are very essential for the development of the neocortex (9, 19). During corticogenesis, neuroblasts undergo active mitosis in the ventricular germinal zone between embryonic day 10 (E10) and E17. Neurons born subsequently migrate radially and for...

Aberrant fear is a cornerstone of several psychiatric disorders. Consequently, there is large interest in elucidation of signaling mechanisms that link extracellular cues to changes in neuronal function and structure in brain pathways that are important in the generation and maintenance of fear memory and its behavioral expression. Members of the Plexin-B family of receptors for class 4 semaphorins play important roles in developmental plasticity of neurons, and their expression persists in some areas of the adult nervous system. Here, we aimed to elucidate the role of Semaphorin 4C (Sema4C) and its cognate receptor, Plexin-B2, in the expression of contextual and cued fear memory, setting a mechanistic focus on structural plasticity and exploration of contributing signaling pathways. We observed that Plexin-B2 and Sema4C are expressed in forebrain areas related to fear memory, such as the anterior cingulate cortex, amygdala and the hippocampus, and their expression is regulated by aversive stimuli that induce fear memory. By generating forebrain-specific Plexin-B2 knockout mice and analyzing fear-related behaviors, we demonstrate that Sema4C-PlexinB2 signaling plays a crucial functional role in the recent and remote recall of fear memory. Detailed neuronal morphological analyses revealed that Sema4C-PlexinB2 signaling largely mediates fear-induced structural plasticity by enhancing dendritic ramifications and modulating synaptic density in the adult hippocampus. Analyses on signaling-related mutant mice showed that these functions are mediated by PlexinB2-dependent RhoA activation. These results deliver important insights into the mechanistic understanding of maladaptive plasticity in fear circuits and have implications for novel therapeutic strategies against fear-related disorders.

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