New views on retinal axon development: a navigation guide

The eye is a peripheral outpost of the central nervous system (CNS) where the retinal ganglion cells (RGCs) reside. RGC axons navigate to their targets in a remarkably stereotyped and error-free manner and it is this process of directed growth that underlies the complex organization of the adult brain. The RGCs are the only retinal neurons to project into the brain and their peripheral location makes them an unusually accessible population of projection neurons for experiments involving in vivo gene transfer, anatomical tracing, transplantation and in vitro culture. In this paper, we review recent findings that have contributed to our understanding of some of the guidance decisions that axons make in the developing visual system. We look at two choice points in the pathway, the optic nerve head (onh) and the midline chiasm, and discuss evidence that supports the idea that key molecules in guiding axon growth at these junctures are netrin-1 (onh) and ephrin-B (chiasm). In the optic tectum where RGC axon terminals are arrayed in topographic order, we present experimental evidence to suggest that in the dorso-ventral dimension, the B-type ephrins and Eph receptors are of prime importance, possibly through attractive interactions. This complements the anterior-posterior topographic mapping known to be mediated through A-type ephrin/Eph repulsive interactions. An emerging theme is that guidance molecules such as ephrin-B and netrin-1 have complex patterns of restricted expression in the pathway and play multiple and changing roles in axon guidance.     

Selective modulation of CD4+ T cells from lupus patients by a promiscuous, protective peptide analog

A peptide encompassing residues 131-151 of the spliceosomal U1-70K protein and its analog phosphorylated at Ser140 were synthesized as potential candidates for the treatment of patients with lupus. Studies in the MRL/lpr and (NZB x NZW)F1 lupus models have demonstrated that these sequences contain a CD4+ T cell epitope but administration of the phosphorylated peptide only ameliorates the clinical manifestations of treated MRL/lpr mice. Binding assays with soluble HLA class II molecules and molecular modeling experiments indicate that both peptides behave as promiscuous epitopes and bind to a large panel of human DR molecules. In contrast to normal T cells and T cells from non-lupus autoimmune patients, we found that PBMCs from 40% of lupus patients selected randomly and CFSE-labeled CD4+ T cells proliferate in response to peptide 131-151. Remarkably, however, we observed that phosphorylation of Ser140 prevents CD4+ T cells proliferation but not secretion of regulatory cytokines, suggesting a striking immunomodulatory effect of phosphorylated analog on lupus CD4+ T cells that was unique to patients. The analog might act as an activator of regulatory T cells or as a partial agonist of TCR.     

LAP proteins: new gatekeepers of epithelial homeostasis

Cell proliferation and cell differentiation are balanced processes required for the correct development and maintenance of tissues, including epithelial tissues. Disruption of this balance by downregulation or loss of function of gatekeepers of epithelial homeostasis may unleash tumor suppressing activities leading ultimately to tumorigenesis. Among the newcoming actors involved in epithelial cell polarity, recent data shed light on the crucial role played by the LAP (LRR And PDZ) protein family. LAP proteins assemble receptors, cytoplasmic adaptors and enzymes in multimolecular networks important for the different steps of epithelial differentiation : adhesion, building of tight junctions and trafficking of proteins along the secretory pathway. Furthermore, genetic studies in invertebrates and vertebrates have installed LAP proteins not only as crucial determinants for epithelial integrity but also as key regulators of cell proliferation and embryonic development.     

Topographic mapping in dorsoventral axis of the Xenopus retinotectal system depends on signaling through ephrin-B ligands

Ephrin-B and EphB are distributed in matching dorsoventral gradients in the embryonic Xenopus visual system with retinal axons bearing high levels of ligand (dorsal) projecting to tectal regions with high receptor expression (ventral). In vitro stripe assays show that dorsal retinal axons prefer to grow on EphB receptor stripes supporting an attractive guidance mechanism. In vivo disruption of EphB/ephrin-B function by application of exogenous EphB or expression of dominant-negative ephrin-B ligand in dorsal retinal axons causes these axons to shift dorsally in the tectum, while misexpression of wild-type ephrin-B in ventral axons causes them to shift ventrally. These dorsoventral targeting errors are consistent with the hypothesis that an attractive mechanism that requires ephrin-B cytoplasmic domain is critical for retinotectal mapping in this axis.     

Identification of visual paternity cues in humans

Understanding how individuals identify their relatives has implications for the evolution of social behaviour. Kinship cues might be based on familiarity, but in the face of paternity uncertainty and costly paternal investment, other mechanisms such as phenotypic matching may have evolved. In humans, paternal recognition of offspring and subsequent discriminative paternal investment have been linked to father–offspring facial phenotypic similarities. However, the extent to which paternity detection is impaired by environmentally induced facial information is unclear. We used 27 portraits of fathers and their adult sons to quantify the level of paternity detection according to experimental treatments that manipulate the location, type and quantity of visible facial information. We found that (i) the lower part of the face, that changes most with development, does not contain paternity cues, (ii) paternity can be detected even if relational information within the face is disrupted and (iii) the signal depends on the presence of specific information rather than their number. Taken together, the results support the view that environmental effects have little influence on the detection of paternity using facial similarities. This suggests that the cognitive dispositions enabling the facial detection of kinship relationships ignore genetic irrelevant facial information.     

Presence of normal human cell surface antigens in plasma of athymic mice bearing a human colon carcinoma and in normal human plasma

Summary The mixed haemadsorption (MHA) method was employed for detection of several normal antigenic components on the surface of human colon carcinoma cells (HT-29). The antigens were expressed by cells in monolayer cultures and in suspensions prepared by monolayer trypsinization, and by cells of tumours growing progressively in athymic mice. The plasma of such animals bearing medium sized and large, non-necrotic tumours contained all the antigens, as determined by the radial diffusion immune haemolysis method (RDIH); the plasma of animals with small or large heavily necrotic tumours did not contain detectable amounts of any of the determinants. The half-life of the determinants in the circulation as extracellular entities was ca. 20 h. The same antigens, and fibronectin, were found to be ubiquitously represented in normal human plasma. It is proposed that the presence of membrane antigens in plasma is the result of physiological shedding of cell surface constituents by living cells.