The correct navigation of axons to their targets depends on guidance molecules in the extra-cellular environment. Differential responsiveness to a particular guidance cue is largely an outcome of disparity in the expression of its receptors on the reacting axons. Here, we show that the differential responsiveness of sympathetic and sensory neurons to the transmembrane Semaphorin Sema6A is mainly determined by its co-expression in the responding neurons. Both sympathetic and sensory neurons express the Sema6A receptor Plexin-A4, but only sympathetic neurons respond to it. The expression of Sema6A counteracts this responsiveness and is detected only in sensory neurons. Remarkably, sensory neurons that lack Sema6A gain sensitivity to it in a Plexin-A4-dependent manner. Using heterologus systems, we show that the co-expression of Sema6A and Plexin-A4 hinders the binding of exogenous ligand, suggesting that a Sema6A-Plexin-A4 cis interaction serves as an inhibitory mechanism. Finally, we provide evidence for differential modes of interaction in cis versus in trans. Thus, co-expression of a transmembrane cue together with its receptor can serve as a guidance response modulator.

Guidance receptor signaling is crucial for neural circuit formation and elicits diverse cellular events in specific neurons. We found that signaling from the guidance cue semaphorin 3A diverged through distinct cytoplasmic domains in its receptor Plexin-A4 to promote disparate cellular behavior in different neuronal cell types. Plexin-A4 has three main cytoplasmic domains--C1, Hinge/RBD, and C2--and interacts with family members of the Rho guanine nucleotide exchange factor FARP proteins. We show that growth cone collapse occurred in Plexin-A4-deficient dorsal root ganglion sensory neurons reconstituted with Plexin-A4 containing either the Hinge/RBD or C2 domain, whereas both of the Hinge/RBD and C1 domains were required for dendritic arborization in cortical neurons. Although knockdown studies indicated that both the collapse and arborization responses involved FARP2, mutations in the cytoplasmic region of Plexin-A4 that reduced its interaction with FARP2 strongly inhibited semaphorin 3A-induced dendritic branching but not growth cone collapse, suggesting that different degrees of interaction are required for the two responses or that developing axons have an indirect path to FARP2 activation. Thus, our study provided insights into the multifunctionality of guidance receptors, in particular showing that the semaphorin 3A signal diverges through specific functions of the modular domains of Plexin-A4.

E2F transcription factors play pivotal roles in controlling the expression of genes involved in cell viability as well as genes involved in cell death. E2F1 is an important constituent of this protein family, which thus far contains eight members. The interaction of E2F1 with its major regulator, retinoblastoma protein (Rb), has been studied extensively in the past two decades, concentrating on the role of E2F1 in transcriptional regulation and the role of Rb in cell replication and cancer formation. Additionally, the effect of viral infections on E2F1/Rb interactions has been analyzed for different viruses, concentrating on cell division, which is essential for viral replication. In the present study, we monitored E2F1-Rb interactions during human herpesvirus 6A ( Human herpesvirus 6A (HHV-6A) and HHV-6B were initially isolated from peripheral blood mononuclear cells of immunologically deprived AIDS patients and patients with lymphoproliferative disorders (42, 58). They were recognized as distinct viruses by employing restriction enzyme analyses, antigenicity, and epidemiology (1, 60). Together with HHV-7, they constitute the group of roseoloviruses, a subgroup of the betaherpesvirus subfamily, possessing a colinear gene arrangement (54, 64). HHV-6A, HHV-6B, and HHV-7 associations with diseases have been reviewed recently (24, 37). Both HHV-6A and HHV-6B variants use CD46 as a receptor (59) to gain entry into various types of cells. They replicate productively in cultured CD4 ϩ T cells but also are known to have central nervous system involvement, as reviewed previously (24, 37). HHV-6B infects the majority of children by the age of 2, causing either asymptomatic infections or roseola infantum, characterized by high fever and skin rash. The virus can be isolated from peripheral blood mononuclear cells of the sick children (78, 79). In more rare cases, HHV-6 and HHV-7 infections were reported to cause seizures, convulsions, and encephalopathy (6,49,66,70,77,78,80,82,84). Furthermore, HHV-6B strains were found to be activated from latency in bone marrow, kidney, liver, and other transplantations (9,25,41,55,65,74,81,(83)(84)(85)(86)(87)(88). Of interest is our previous study (55), in which HHV-6B reactivation was prophylactically inhibited by ganciclovir treatment at the onset of transplantation. There is no acute disease currently known to be caused by HHV-6A. Viral isolates were implicated in the aggravation of symptoms of chronic fatigue syndrome and also in a subset of relapsing-remitting multiple sclerosis exacerbations. Recent studies have tested these associations (2-4, 14, 23, 34, 44, 56, 76).In the present paper, we describe the interaction of HHV-6A and HHV-6B with the host cell, concentrating on changes in E2F1/Rb pathways in infected SupT1 T cells. There are eight known members of the E2F family, which function to activate or repress the transcription of different combinations of genes, promoting or inhibiting cell cycle progression (18). The E2F1 transcription factor, originally identified as the cel...