Synapses are regulated by the cytoplasmic tyrosine kinase Fer in a pathway mediated by p120catenin, Fer, SHP-2, and β-catenin

Localization of presynaptic components to synaptic sites is critical for hippocampal synapse formation. Cell adhesion–regulated signaling is important for synaptic development and function, but little is known about differentiation of the presynaptic compartment. In this study, we describe a pathway that promotes presynaptic development involving p120catenin (p120ctn), the cytoplasmic tyrosine kinase Fer, the protein phosphatase SHP-2, and β-catenin. Presynaptic Fer depletion prevents localization of active zone constituents and synaptic vesicles and inhibits excitatory synapse formation and synaptic transmission. Depletion of p120ctn or SHP-2 similarly disrupts synaptic vesicle localization with active SHP-2, restoring synapse formation in the absence of Fer. Fer or SHP-2 depletion results in elevated tyrosine phosphorylation of β-catenin. β-Catenin overexpression restores normal synaptic vesicle localization in the absence of Fer or SHP-2. Our results indicate that a presynaptic signaling pathway through p120ctn, Fer, SHP-2, and β-catenin promotes excitatory synapse development and function

Dielectric Properties of Polypropylene Containing Nano-Particles

Peer reviewed: NoNRC publication: Ye

Distinct but overlapping roles of LRRTM1 and LRRTM2 in developing and mature hippocampal circuits

LRRTMs are postsynaptic cell adhesion proteins that have region-restricted expression in the brain. To determine their role in the molecular organization of synapses in vivo, we studied synapse development and plasticity in hippocampal neuronal circuits in mice lacking both Lrrtm1 and Lrrtm2. We found that LRRTM1 and LRRTM2 regulate the density and morphological integrity of excitatory synapses on CA1 pyramidal neurons in the developing brain but are not essential for these roles in the mature circuit. Further, they are required for long-term-potentiation in the CA3-CA1 pathway and the dentate gyrus, and for enduring fear memory in both the developing and mature brain. Our data show that LRRTM1 and LRRTM2 regulate synapse development and function in a cell-type and developmental-stage-specific manner, and thereby contribute to the fine-tuning of hippocampal circuit connectivity and plasticity

Hyperinsulinemia Drives Diet-Induced Obesity Independently of Brain Insulin Production

SummaryHyperinsulinemia is associated with obesity and pancreatic islet hyperplasia, but whether insulin causes these phenomena or is a compensatory response has remained unsettled for decades. We examined the role of insulin hypersecretion in diet-induced obesity by varying the pancreas-specific Ins1 gene dosage in mice lacking Ins2 gene expression in the pancreas, thymus, and brain. Age-dependent increases in fasting insulin and β cell mass were absent in Ins1+/−:Ins2−/− mice fed a high-fat diet when compared to Ins1+/+:Ins2−/− littermate controls. Remarkably, Ins1+/−:Ins2−/− mice were completely protected from diet-induced obesity. Genetic prevention of chronic hyperinsulinemia in this model reprogrammed white adipose tissue to express uncoupling protein 1 and increase energy expenditure. Normalization of adipocyte size and activation of energy expenditure genes in white adipose tissue was associated with reduced inflammation, reduced fatty acid spillover, and reduced hepatic steatosis. Thus, we provide genetic evidence that pathological circulating hyperinsulinemia drives diet-induced obesity and its complications

Tendinopathy—from basic science to treatment

Chronic tendon pathology (tendinopathy), although common, is difficult to treat. Tendons possess a highly organized fibrillar matrix, consisting of type I collagen and various 'minor' collagens, proteoglycans and glycoproteins. The tendon matrix is maintained by the resident tenocytes, and there is evidence of a continuous process of matrix remodeling, although the rate of turnover varies at different sites. A change in remodeling activity is associated with the onset of tendinopathy. Major molecular changes include increased expression of type III collagen, fibronectin, tenascin C, aggrecan and biglycan. These changes are consistent with repair, but they might also be an adaptive response to changes in mechanical loading. Repeated minor strain is thought to be the major precipitating factor in tendinopathy, although further work is required to determine whether it is mechanical overstimulation or understimulation that leads to the change in tenocyte activity. Metalloproteinase enzymes have an important role in the tendon matrix, being responsible for the degradation of collagen and proteoglycan in both healthy patients and those with disease. Metalloproteinases that show increased expression in painful tendinopathy include ADAM (a disintegrin and metalloproteinase)-12 and MMP (matrix metalloproteinase)-23. The role of these enzymes in tendon pathology is unknown, and further work is required to identify novel and specific molecular targets for therapy

Individual and Contextual Factors of Sexual Risk Behavior in Youth Perinatally Infected with HIV

Abstract This study prospectively examines the effects of maternal and child HIV infection on youth penetrative and unprotected penetrative sex, as well as the role of internal contextual, external contextual, social and self-regulatory factors in influencing the sexual behaviors of HIV?infected (PHIV+), HIV?affected (uninfected with an HIV+ caregiver), and HIV unaffected (uninfected with an HIV? caregiver) youth over time. Data (N=420) were drawn from two longitudinal studies focused on the effects of pediatric or maternal HIV on youth (51% female; 39% PHIV+) and their caregivers (92% female; 46% HIV+). PHIV+ youth were significantly less likely to engage in penetrative sex than HIV? youth at follow-up, after adjusting for contextual, social, and self-regulatory factors. Other individual- and contextual-level factors such as youth alcohol and marijuana use, residing with a biological parent, caregiver employment, caregiver marijuana use, and youth self-concept were also associated with penetrative sex. Youth who used alcohol were significantly more likely to engage in unprotected penetrative sex. Data suggest that, despite contextual, social, and self-regulatory risk factors, PHIV+ youth are less likely to engage in sexual behavior compared to HIV? youth from similar environments. Further research is required to understand delays in sexual activity in PHIV+ youth and also to understand potential factors that promote resiliency, particularly as they age into older adolescence and young adulthood.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98470/1/apc%2E2012%2E0005.pd