A cell–ECM mechanism for connecting the ipsilateral eye to the brain

Information about features in the visual world is parsed by circuits in the retina and is then transmitted to the brain by distinct subtypes of retinal ganglion cells (RGCs). Axons from RGC subtypes are stratified in retinorecipient brain nuclei, such as the superior colliculus (SC), to provide a segregated relay of parallel and feature-specific visual streams. Here, we sought to identify the molecular mechanisms that direct the stereotyped laminar targeting of these axons. We focused on ipsilateral-projecting subtypes of RGCs (ipsiRGCs) whose axons target a deep SC sublamina. We identified an extracellular glycoprotein, Nephronectin (NPNT), whose expression is restricted to this ipsiRGC-targeted sublamina. SC-derived NPNT and integrin receptors expressed by ipsiRGCs are both required for the targeting of ipsiRGC axons to the deep sublamina of SC. Thus, a cell–extracellular matrix (ECM) recognition mechanism specifies precise laminar targeting of ipsiRGC axons and the assembly of eye-specific parallel visual pathways.

Integrin α3β1 Represses Reelin Expression in Breast Cancer Cells to Promote Invasion

Integrin α3β1, a cell adhesion receptor for certain laminins, is known to promote breast tumor growth and invasion. Our previous gene microarray study showed that the RELN gene, which encodes the extracellular glycoprotein Reelin, was upregulated in α3β1-deficient (i.e., α3 knockdown) MDA-MB-231 cells. In breast cancer, reduced RELN expression is associated with increased invasion and poor prognosis. In this study we demonstrate that α3β1 represses RELN expression to enhance breast cancer cell invasion. RELN mRNA was significantly increased upon RNAi-mediated α3 knockdown in two triple-negative breast cancer cell lines, MDA-MB-231 and SUM159. Modulation of baseline Reelin levels altered invasive potential, where enhanced Reelin expression in MDA-MB-231 cells reduced invasion, while RNAi-mediated suppression of Reelin in SUM159 cells increased invasion. Moreover, treatment of α3β1-expressing MDA-MB-231 cells with culture medium that was conditioned by α3 knockdown MDA-MB-231 cells led to decreased invasion. RNAi-mediated suppression of Reelin in α3 knockdown MDA-MB-231 cells mitigated this effect of conditioned-medium, identifying secreted Reelin as an inhibitor of cell invasion. These results demonstrate a novel role for α3β1 in repressing Reelin in breast cancer cells to promote invasion, supporting this integrin as a potential therapeutic target.

From Selenium to Selenoproteins and their Role - Minireview

Selenium (SE) is an essential micronutrient fulfilling a number of biological roles, being integrated as selenocysteine in the primary structure of certain selenoproteins. The Selenocysteine is synthesized and inserted into proteins during the translational process of the RNAm by a mechanism which involves converting a stop codon for certain proteins into a meaningful codon. Only 25 genes encoding selenocysteine-incorporating proteins have been identified in the human genome. The selenoprotein families including glutathione peroxidase, iodothyronine deiodinase and thioredoxin reductases are known as enzymes engaged in redox processes. The selenoprotein P (SEPP1) is a hepatokine produced by the liver, an extracellular glycoprotein, which is not part of these families. The purpose of this Article is to present the form of distribution of selenium and its physiological role in the body.

Thrombospondin-1: A Key Protein That Induces Fibrosis in Diabetic Complications

Fibrosis accompanies most common pathophysiological features of diabetes complications in different organs. It is characterized by an excessive accumulation of extracellular matrix (ECM) components, the response to which contributes to inevitable organ injury. The extracellular protein thrombospondin-1 (TSP-1), a kind of extracellular glycoprotein, is upregulated by the increased activity of some transcription factors and results in fibrosis by activating multiple pathways in diabetes. The results of studies from our team and other colleagues indicate that TSP-1 is associated with the pathological process leading to diabetic complications and is considered to be the most important factor in fibrosis. This review summarizes the molecular mechanism of increased TSP-1 induced by hyperglycemia and the role of TSP-1 in fibrosis during the development of diabetes complications.

The Expression of Thrombospondin-4 Correlates with Disease Severity in Osteoarthritic Knee Cartilage

Osteoarthritis (OA) is a progressive joint disease characterized by a continuous degradation of the cartilage extracellular matrix (ECM). The expression of the extracellular glycoprotein thrombospondin-4 (TSP-4) is known to be increased in injured tissues and involved in matrix remodeling, but its role in articular cartilage and, in particular, in OA remains elusive. In the present study, we analyzed the expression and localization of TSP-4 in healthy and OA knee cartilage by reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry, and immunoblot. We found that TSP-4 protein expression is increased in OA and that expression levels correlate with OA severity. TSP-4 was not regulated at the transcriptional level but we detected changes in the anchorage of TSP-4 in the altered ECM using sequential protein extraction. We were also able to detect pentameric and fragmented TSP-4 in the serum of both healthy controls and OA patients. Here, the total protein amount was not significantly different but we identified specific degradation products that were more abundant in sera of OA patients. Future studies will reveal if these fragments have the potential to serve as OA-specific biomarkers.

The Correlation between FSTL1 Expression and Airway Remodeling in Asthmatics

Background. Asthma is characterized by airway remodeling. Follistatin-like protein 1 (FSTL1) is an extracellular glycoprotein. Recent studies suggest that FSTL1 may participate in the pathogenesis of asthma. Objectives. To analyze the association between FSTL1 and some parameters and inspect the role of FSTL1 in asthma. Methods. We examined FSTL1 levels in 32 asthmatics and 25 controls. All subjects enrolled had routine blood tests, spirometry, and impulse oscillometry performed. Additionally, 15 of the 32 asthmatics underwent fibre optic bronchoscopy. Spearman rank analysis was performed to detect the correlation between FSTL1 and other parameters. Results. Plasma FSTL1 levels were higher in asthmatics (130.762 ± 46.029 ng/mL) than in controls (95.408 ± 33.938 ng/mL) (p=0.009). Plasma FSTL1 levels were associated with fibrosis levels around the airways (rs=0.529, p=0.043) and α-smooth muscle actin (α-SMA) (rs=0.554, p=0.032). FSTL1 levels in bronchoalveolar lavage fluid were associated with collagen I (rs=0.536, p=0.040), α-SMA (rs=0.561, p=0.029), fibrosis levels (rs=0.779, p=0.001), and the thickness of the airway reticular basement membrane (RBM) (rs=0.660, p=0.007). Conclusions. FSTL1 levels in asthmatics were linked with increased smooth muscle mass and thickened RBM. FSTL1 may contribute to airway remodeling in asthmatics.

Osteopontin O-glycosylation contributes to its phosphorylation and cell-adhesion properties

Osteopontin is a multiphosphorylated extracellular glycoprotein that has important roles in various physiological and pathological phenomena. We demonstrate that osteopontin O-glycosylation affects its phosphorylation status, cell-spreading and -adhesion activities, and its association with β1 integrins.