The six members of the contactin (CNTN) family of neural cell adhesion molecules are involved in the formation and maintenance of the central nervous system (CNS) and have been linked to mental retardation and neuropsychiatric disorders such as autism. Five of the six CNTNs bind to the homologous receptor protein tyrosine phosphatases gamma (PTPRG) and zeta (PTPRZ), but the biological roles of these interactions remain unclear. We report here the cocrystal structure of the carbonic anhydrase-like domain of PTPRZ bound to tandem Ig repeats of CNTN1 and combine these structural data with binding assays to show that PTPRZ binds specifically to CNTN1 expressed at the surface of oligodendrocyte precursor cells. Furthermore, analyses of glial cell populations in wild-type and PTPRZ-deficient mice show that the binding of PTPRZ to CNTN1 expressed at the surface of oligodendrocyte precursor cells inhibits their proliferation and promotes their development into mature oligodendrocytes. Overall, these results implicate the PTPRZ/CNTN1 complex as a previously unknown modulator of oligodendrogenesis.

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In order to gain insight into the biological role of receptor protein tyrosine phosphatase ␥ (RPTP␥), we have generated RPTP␥-null mice. RPTP␥ was disrupted by insertion of the ␤-galactosidase gene under the control of the RPTP␥ promoter. As the RPTP␥-null mice did not exhibit any obvious phenotype, we made use of these mice to study RPTP␥ expression and thus shed light on potential biological functions of this phosphatase. Inspection of mouse embryos shows that RPTP␥ is expressed in a variety of tissues during embryogenesis. RPTP␥ is expressed in both embryonic and adult brains. Specifically, we detected RPTP␥ expression in cortical layers II and V and in the stratum pyramidale of the hippocampus, indicating that RPTP␥ is a marker for pyramidal neurons. Mixed primary culture of glial cells showed a lack of expression of RPTP␥ in astrocytes and a low expression of RPTP␥ in oligodendrocytes and in microglia. Interestingly, RPTP␥ expression was detected in all sensory organs, including the ear, nose, tongue, eye, and vibrissa follicles, suggesting a potential role of RPTP␥ in sensory neurons. An initial behavioral analysis showed minor changes in the RPTP␥-null mice.The phosphorylation of proteins on tyrosine residues is essential for transmission of signals for cell growth, proliferation, and differentiation. Phosphorylation depends on a regulated balance between the activities of protein tyrosine kinases and protein tyrosine phosphatases (PTP). While the roles and the mechanisms of action of tyrosine kinases are well characterized, our present understanding of tyrosine phosphatases is less developed.PTP are classified into two groups, one comprising cytoplasmic and the other transmembrane, or receptor type (receptor protein tyrosine phosphatases [RPTP]), proteins. Seven different classes of RPTP have been defined, based primarily upon variations in the extracellular domain (reviewed in references 2 and 9). RPTP have one or more intracellular catalytic domains with a conserved cysteine at the active site, a transmembrane region, and an extracellular domain. We have focused our studies on RPTP␥, a receptor-type PTP containing an extracellular carbonic anhydrase domain, a fibronectin type III domain, and a spacer domain (1). RPTP␥ is representative of a subfamily of RPTP that includes RPTP (also designated RPTP␤). As is the case for RPTP, several isoforms have been described for RPTP␥ (19). RPTP␥-B lacks 29 amino acids in a cytosolic helix-turn-helix like motif in the juxtamembrane position compared to the full-length RPTP␥-A isoform. RPTP␥-C contains only one phosphatase domain, while RPTP␥-D is a soluble isoform and has lost all phosphatase activity.Very few studies have reported on the biological function of RPTP␥. Overexpression of RPTP␥-A in the neuronal PC12D cell line prevented neurite outgrowth upon nerve growth factor (NGF) treatment (20). Both interleukin 1␤ and tumor necrosis factor upregulate RPTP␥ mRNA in astrocytoma cell lines, suggesting a potential role for RPTP␥ in the development of inflammatory d...

Main Text (excl abstract, refs, figure legends, acknows) = 3992 words 2 Abbreviations, BCI, BCM, -cell imaging and mass, respectively; IMIDIA, Innovative Medicines Initiative in DIAbetes; MRI, magnetic resonance imaging; OPT, optical projection tomography; PET, positron emission tomography; SPECT, single photon emission computed tomography; VMAT, vesicular monoamine transporter; GLP1, glucagon-like peptide-1; PSA-NCAM, polysialylated neural cell adhesion molecule; SUR 1, sulfonylurea receptor 1; STZ, streptozotocin; T1D type 1 diabetes; T2D, type 2 diabetes; TMEM27, transmembrane protein 27; USPIO, ultrasmall superparamagnetic iron oxide 3 AbstractDiabetes mellitus is a growing worldwide epidemic currently affecting 1 in 12 adults.Treatment of disease complications typically consumes ~10% of healthcare budgets in developed societies. Whilst immune-mediated destruction of insulin-secreting pancreatic -cells is responsible for Type 1 diabetes, both the loss and dysfunction of these cells underlies the more prevalent Type 2 diabetes. The establishment of robust drug development programmes aiming at -cell restoration is still hampered by the absence of means to measure -cell mass prospectively in vivo, an approach which would provide new opportunities for understanding disease mechanisms and ultimately assigning personalized treatments. Here, we describe progress towards this goal achieved by the Innovative Medicines Initiative in DIAbetes (IMIDIA), a collaborative public-private consortium supported by the European Commission and dedicated resources of pharmaceutical companies. We compare several of the available imaging modalities and molecular targets and provide suggestions as to the likeliest to lead to tractable approaches and furthermore we discuss the simultaneous development of animal models that can be used to measure subtle changes in -cell mass, a prerequisite for validating the clinical potential of the different imaging tracers.4

OBJECTIVEWe studied whether manganese-enhanced high-field magnetic resonance (MR) imaging (MEHFMRI) could quantitatively detect individual islets in situ and in vivo and evaluate changes in a model of experimental diabetes.RESEARCH DESIGN AND METHODSWhole pancreata from untreated (n = 3), MnCl2 and glucose-injected mice (n = 6), and mice injected with either streptozotocin (STZ; n = 4) or citrate buffer (n = 4) were imaged ex vivo for unambiguous evaluation of islets. Exteriorized pancreata of MnCl2 and glucose-injected mice (n = 6) were imaged in vivo to directly visualize the gland and minimize movements. In all cases, MR images were acquired in a 14.1 Tesla scanner and correlated with the corresponding (immuno)histological sections.RESULTSIn ex vivo experiments, MEHFMRI distinguished different pancreatic tissues and evaluated the relative abundance of islets in the pancreata of normoglycemic mice. MEHFMRI also detected a significant decrease in the numerical and volume density of islets in STZ-injected mice. However, in the latter measurements the loss of β-cells was undervalued under the conditions tested. The experiments on the externalized pancreata confirmed that MEHFMRI could visualize native individual islets in living, anesthetized mice.CONCLUSIONSData show that MEHFMRI quantitatively visualizes individual islets in the intact mouse pancreas, both ex vivo and in vivo.