Faculty Bibliography

In myelinating Schwann cells, E-cadherin is a component of the adherens junctions that stabilize the architecture of the noncompact myelin region. In other cell types, E-cadherin has been considered as a signaling receptor that modulates intracellular signal transduction and cellular responses. To determine whether E-cadherin plays a regulatory role during Schwann cell myelination, we investigated the effects of E-cadherin deletion and over-expression in Schwann cells. In vivo, Schwann cell-specific E-cadherin ablation results in an early myelination delay. In Schwann cell-dorsal root ganglia neuron co-cultures, E-cadherin deletion attenuates myelin formation and shortens the myelin segment length. When over-expressed in Schwann cells, E-cadherin improves myelination on Nrg1 type III+/- neurons and induces myelination on normally non-myelinated axons of sympathetic neurons. The pro-myelinating effect of E-cadherin is associated with an enhanced Nrg1-erbB receptor signaling, including activation of the downstream Akt and Rac. Accordingly, in the absence of E-cadherin, Nrg1-signaling is diminished in Schwann cells. Our data also show that E-cadherin expression in Schwann cell is induced by axonal Nrg1 type III, indicating a reciprocal interaction between E-cadherin and the Nrg1 signaling. Altogether, our data suggest a regulatory function of E-cadherin that modulates Nrg1 signaling and promotes Schwann cell myelin formation. GLIA 2015.

BACKGROUND: Patients undergoing cardiovascular procedures remain at increased risk for myocardial infarction, stroke, and cardiovascular death. Risk factor control in this patient population remains suboptimal and would likely benefit from strategies targeting education, lifestyle, and healthy behaviors. DESIGN: The IMPACT trial is a 400-subject prospective randomized trial designed to compare different cardiovascular prevention strategies in subjects following a cardiovascular intervention. The trial began enrollment in the Spring of 2012 and is randomizing subjects in a 1:1:1 manner to usual care, a one-time cardiovascular prevention consult, or a one-time cardiovascular prevention consult plus behavioral intervention program (telephone-based motivational interviewing and tailored text messages) over a 6-month period. The primary end point is non-high-density lipoprotein cholesterol. Secondary end points include other plasma lipid values, metabolic risk, smoking cessation, physical activity, dietary intake, medication use and adherence, and quality of life. CONCLUSIONS: The IMPACT trial provides data on different management strategies for risk factor optimization in subjects following cardiovascular procedures. The results will provide a platform for the continued development of novel multidisciplinary interventions in this high-risk population.

SCOPE: The increased prevalence of cardiovascular diseases (CVDs) has been hypothesized to be the result of an increased exposure to a host of atherogenic environmental factors, paramount among them being unhealthy dietary habits. Long-chain n-3 polyunsaturated fatty acids (PUFAs) have been shown to have cardio protective effects, partially due to their ability to regulate gene expression. In this regard, increasing attention has been devoted to the role of miRNAs as regulators of multiple metabolic pathways whose deregulation has been associated with CVD risk. In this work we investigated whether miRNA expression was regulated by docosahexanoic acid, conjugated linoleic acid and cholesterol in Caco-2 cells. RESULTS: Among the modulated miRNAs, miR-107 was differentially expressed by all treatments and this modulation was independent of its hosting gene, panthothenate kinase 1, possibly through its own promoter, which contains binding sites for metabolically relevant transcription factors. Among the putative target genes of miR-107, we found some genes with key roles in circadian rhythm. Specifically, we demonstrated that binding of miR-107 to the circadian locomotor output cycles kaput gene results in the deregulation of the circadian rhythm of the cells. CONCLUSION: Since chronodisruption has been linked to metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and CVD, our findings suggest that miR-107 could represent a new approach for pharmacological treatment of these diseases.

Toll-like receptors (TLRs) play critical roles in innate immunity in many animal species. The sole TLR of C. elegans-TOL-1-is required for a pathogen-avoidance behavior, yet how it promotes this behavior is unknown. We show that for pathogen avoidance TOL-1 signaling is required in the chemosensory BAG neurons, where it regulates gene expression and is necessary for their chemosensory function. Genetic studies revealed that TOL-1 acts together with many conserved components of TLR signaling. BAG neurons are activated by carbon dioxide (CO2), and we found that this modality is required for pathogen avoidance. TLR signaling can therefore mediate host responses to microbes through an unexpected mechanism: by promoting the development and function of chemosensory neurons that surveil the metabolic activity of environmental microbes.

The p75 neurotrophin receptor (p75(NTR)) is a multifunctional receptor that participates in many critical processes in the nervous system, ranging from apoptosis to synaptic plasticity and morphological events. It is a member of the tumor necrosis factor receptor (TNFR) superfamily, whose members undergo trimeric oligomerization. Interestingly, p75(NTR) interacts with dimeric ligands (i.e., proneurotrophins or mature neurotrophins), but several of the intracellular adaptors that mediate p75(NTR) signaling are trimeric (i.e., TNFR-associated factor 6 or TRAF6). Consequently, the active receptor signaling unit remains uncertain. To identify the functional receptor complex, we evaluated its oligomerization in vitro and in mice brain tissues using a combination of biochemical techniques. We found that the most abundant homotypic arrangement for p75(NTR) is a trimer and that monomers and trimers coexist at the cell surface. Interestingly, trimers are not required for ligand-independent or ligand-dependent p75(NTR) activation in a growth cone retraction functional assay. However, monomers are capable of inducing acute morphological effects in neurons. We propose that p75(NTR) activation is regulated by its oligomerization status and its levels of expression. These results indicate that the oligomeric state of p75(NTR) confers differential responses and offers an explanation for the diverse and contradictory actions of this receptor in the nervous system. SIGNIFICANCE STATEMENT: The p75 neurotrophin receptor (p75(NTR)) regulates a wide range of cellular functions, including apoptosis, neuronal processes remodeling, and synaptic plasticity. The goal of our work was to inquire whether oligomers of the receptor are required for function. Here we report that p75(NTR) predominantly assembles as a trimer, similar to other tumor necrosis factor receptors. Interestingly, monomers and trimers coexist at the cell surface, but trimers are not required for p75(NTR) activation in a functional assay. However, monomers are capable of inducing acute morphological effects in neurons. Identification of the oligomerization state of p75(NTR) begins to provide insights to the mechanisms of signal initiation of this noncatalytic receptor, as well as to develop therapeutic interventions to diminish its activity.

BACKGROUND: Male circumcision (MC) has been demonstrated to be effective and cost-effective for HIV/AIDS prevention. Global guidance to adopt this intervention was announced in 2007 for countries with high HIV/AIDS prevalence and low MC prevalence. However, scale up of voluntary medical male circumcision (VMMC) programs in MC priority countries have been slow. Many of these countries have particular cultural barriers that impede uptake of this effective intervention. This analysis explored correlates of MC status among men and their socio-economic, health and sexual behaviour factors using DHS data (2006-2011) from 11 MC priority countries. METHODS: Our analysis included univariate unadjusted analyses for individual countries and the region (by combining all countries into one dataset) and a multiple logistic regression model. RESULTS: Individual country results vary widely but alignment was mostly found between unadjusted analyses and multiple logistic regression model. The model found that men who are of the Muslim faith, reside in urban areas, have higher or secondary education attainment, hold professional occupations, and be in the richest wealth quintile are more likely to be circumcised. Circumcision is also positively correlated with lower reports of STIs, safe sexual behaviour, and HIV/AIDS prevention knowledge. CONCLUSIONS: Since the data collected predate VMMC program launch in these countries, results can only indicate baseline associations. However, characteristics of these existing circumcision practices may be utilized for better population targeting and program management to achieve higher impact with this effective prevention strategy.

Many proteins are known to promote ciliogenesis, but mechanisms that promote primary cilia disassembly before mitosis are largely unknown. Here we identify a mechanism that favours cilium disassembly and maintains the disassembled state. We show that co-localization of the S/G2 phase kinase, Nek2 and Kif24 triggers Kif24 phosphorylation, inhibiting cilia formation. We show that Kif24, a microtubule depolymerizing kinesin, is phosphorylated by Nek2, which stimulates its activity and prevents the outgrowth of cilia in proliferating cells, independent of Aurora A and HDAC6. Our data also suggest that cilium assembly and disassembly are in dynamic equilibrium, but Nek2 and Kif24 can shift the balance toward disassembly. Further, Nek2 and Kif24 are overexpressed in breast cancer cells, and ablation of these proteins restores ciliation in these cells, thereby reducing proliferation. Thus, Kif24 is a physiological substrate of Nek2, which regulates cilia disassembly through a concerted mechanism involving Kif24-mediated microtubule depolymerization.

The pharyngeal arch arteries (PAAs) are a series of paired embryonic blood vessels that give rise to several major arteries that connect directly to the heart. During development, the PAAs emerge from nkx2.5-expressing mesodermal cells and connect the dorsal head vasculature to the outflow tract of the heart. Despite their central role in establishing the circulatory system, the embryonic origins of the PAA progenitors are only coarsely defined, and the factors that specify them and their regenerative potential are unclear. Using fate mapping and mutant analysis, we find that PAA progenitors are derived from the tcf21 and nkx2.5 double-positive head mesoderm and require these two transcription factors for their specification and survival. Unexpectedly, cell ablation shows that the tcf21+; nkx2.5+ PAA progenitors are not required for PAA formation. We find that this compensation is due to the replacement of ablated tcf21+; nkx2.5+ PAA cells by endothelial cells from the dorsal head vasculature. Together, these studies assign the embryonic origin of the great vessel progenitors to the interface between the pharyngeal and cardiac mesoderm, identify the transcription factor code required for their specification, and reveal an unexpected plasticity in the formation of the great vessels.