Little is known about the architecture of cellular microenvironments that support stem and precursor cells during tissue development. Although adult stem cell niches are organized by specialized ...supporting cells, in the developing cerebral cortex, neural stem/precursor cells reside in a neurogenic niche lacking distinct supporting cells. Here, we find that neural precursors themselves comprise the niche and regulate their own development. Precursor-precursor contact regulates β-catenin signaling and cell fate. In vivo knockdown of N-cadherin reduces β-catenin signaling, migration from the niche, and neuronal differentiation in vivo. N-cadherin engagement activates β-catenin signaling via Akt, suggesting a mechanism through which cells in tissues can regulate their development. These results suggest that neural precursor cell interactions can generate a self-supportive niche to regulate their own number.
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► Cortical ventricular zone neural precursors exhibit β-catenin signaling ► N-cadherin maintains β-catenin signaling in cortical precursors ► N-cadherin regulates neuronal differentiation and cell cycle exit via β-catenin ► N-cadherin signals through Akt and phosphor-Ser552 of β-catenin
Progenitor cells that express the transcription factor olig1 generate several neural cell types including oligodendrocytes and GABAergic interneurons in the dorsal cortex. The fate of these ...progenitor cells is regulated by a number of signals including bone morphogenetic proteins (BMPs) secreted in the dorsal forebrain. BMPs signal by binding to heteromeric serine-threonine kinase receptors formed by type I (BMPR1a, BMPR1b, Alk2) and type II (BMPRII) subunits. To determine the specific role of the BMPR1a subunit in lineage commitment by olig1-expressing cells, we used a cre/loxP genetic approach to ablate BMPR1a in these cells while leaving signaling from other subunits intact. There was a reduction in numbers of immature oligodendrocytes in the BMPR1a-null mutant brains at birth. However, by postnatal day 20, the BMPR1a-null mice had a significant increase in the number of mature and immature oligodendrocytes compared with wild-type littermates. There was also an increase in the proportion of calbindin-positive interneurons in the dorsomedial cortex of BMPR1a-null mice at birth without any change in the number of parvalbumin- or calretinin-positive cells. These effects were attributable, at least in part, to a decrease in the length of the cell cycle in subventricular zone progenitor cells. Thus, our findings indicate that BMPR1a mediates the suppressive effects of BMP signaling on oligodendrocyte lineage commitment and on the specification of calbindin-positive interneurons in the dorsomedial cortex.
Little is known about the architecture of cellular microenvironments that support stem and precursor cells during tissue development. Although adult stem cell niches are organized by specialized ...supporting cells, in the developing cerebral cortex, neural stem/precursor cells reside in a neurogenic niche lacking distinct supporting cells. Here, we find that neural precursors themselves comprise the niche and regulate their own development. Precursor-precursor contact regulates b-catenin signaling and cell fate. In vivo knockdown of N-cadherin reduces b-catenin signaling, migration from the niche, and neuronal differentiation in vivo. N-cadherin engagement activates b-catenin signaling via Akt, suggesting a mechanism through which cells in tissues can regulate their development. These results suggest that neural precursor cell interactions can generate a self-supportive niche to regulate their own number. Highlights - Cortical ventricular zone neural precursors exhibit b-catenin signaling N-cadherin maintains b-catenin signaling in cortical precursors N-cadherin regulates neuronal differentiation and cell cycle exit via b-catenin N-cadherin signals through Akt and phosphor-Ser552 of b-catenin
Roundabout guidance receptor 2 (ROBO2) plays an important role during early kidney development. ROBO2 is expressed in podocytes, inhibits nephrin-induced actin polymerization, down-regulates ...nonmuscle myosin IIA activity, and destabilizes kidney podocyte adhesion. However, the role of ROBO2 during kidney injury, particularly in mature podocytes, is not known. Herein, we report that loss of ROBO2 in podocytes Robo2 conditional knockout (cKO) mouse is protective from glomerular injuries. Ultrastructural analysis reveals that Robo2 cKO mice display less foot process effacement and better-preserved slit-diaphragm density compared with wild-type littermates injured by either protamine sulfate or nephrotoxic serum (NTS). The Robo2 cKO mice also develop less proteinuria after NTS injury. Further studies reveal that ROBO2 expression in podocytes is up-regulated after glomerular injury because its expression levels are higher in the glomeruli of NTS injured mice and passive Heymann membranous nephropathy rats. Moreover, the amount of ROBO2 in the glomeruli is also elevated in patients with membranous nephropathy. Finally, overexpression of ROBO2 in cultured mouse podocytes compromises cell adhesion. Taken together, these findings suggest that kidney injury increases glomerular ROBO2 expression that might compromise podocyte adhesion and, thus, loss of Robo2 in podocytes could protect from glomerular injury by enhancing podocyte adhesion that helps maintain foot process structure. Our findings also suggest that ROBO2 is a therapeutic target for podocyte injury and podocytopathy.
Primary glomerulocystic kidney disease is a special form of renal cystic disorder characterized by Bowman’s space dilatation in the absence of tubular cysts. ZEB2 is a SMAD-interacting transcription ...factor involved in Mowat-Wilson syndrome, a congenital disorder with an increased risk for kidney anomalies. Here we show that deletion of Zeb2 in mesenchyme-derived nephrons with either Pax2-cre or Six2-cre causes primary glomerulocystic kidney disease without tubular cysts in mice. Glomerulotubular junction analysis revealed many atubular glomeruli in the kidneys of Zeb2 knockout mice, which explains the presence of glomerular cysts in the absence of tubular dilatation. Gene expression analysis showed decreased expression of early proximal tubular markers in the kidneys of Zeb2 knockout mice preceding glomerular cyst formation, suggesting that defects in proximal tubule development during early nephrogenesis contribute to the formation of congenital atubular glomeruli. At the molecular level, Zeb2 deletion caused aberrant expression of Pkd1, Hnf1β, and Glis3, three genes causing glomerular cysts. Thus, Zeb2 regulates the morphogenesis of mesenchyme-derived nephrons and is required for proximal tubule development and glomerulotubular junction formation. Our findings also suggest that ZEB2 might be a novel disease gene in patients with primary glomerular cystic disease.
Diatoms are considered unicellular eukaryotic organisms exclusively depositing biogenic silica. Heretofore there has been no report of calcification by these algae. Here it is shown that calcium ...carbonate within the stalks of Didymosphenia geminata, a nuisance species that has prolifically colonized streams and rivers globally, is biogenic in origin and occurs as a network of calcite nanofibers. The nanofibrous framework in the mineralized polysaccharide matrix imparts mechanical support to the stalks, providing stability in variable flow conditions. The results demonstrate that D. geminata possesses cellular and periplasmic carbonic‐anhydrases that contribute to carbon fixation and biomineralization, respectively. The activity of external carbonic‐anhydrase was more than 50% of the total activity, which points to its role in anchoring this bioeroding diatom on hard surfaces. The first evidence of multiphase biomineralization by diatoms that deposit both biogenic silica and crystalline biogenic calcite which are imparting distinct functional advantage to the organism is provided.
Calcification by diatoms is demonstrated for the first time. The polysaccharide‐based adhesive stalks of Didymosphenia geminata represent a unique biocomposite containing amorphous silica and nanocrystalline calcite fibers. These are produced as a result of the activity of periplasmic carbonic anhydrases which also alters the pH of the cell‐substrate interface leading to bioerosion and biomineralization.
•Enhancement of catalytic activity of Ir with low Se coverages toward O2 reduction.•Formation of oxo-groups on iridium is suppressed upon exposure to selenourea.•Slight increase of the H2O2 formation ...after deposition of selenium on iridium.•Higher tolerance of Se-modified Ir to presence of methanol and ethanol.•In presence of formic acid, decreased selectivity of Ir after modification with Se.
Carbon-supported selenium-modified iridium nanoparticles have been synthesized using IrCl3 and selenourea serving as a precursor of selenium and nitrogen atoms. Here nanostructured iridium is chosen as model base metal for fundamental catalytic considerations because it exhibits interfacial properties resembling both platinum and ruthenium. The systems' electrocatalytic properties have been studied in sulfuric acid electrolyte toward reduction of oxygen and formation of hydrogen peroxide intermediate in comparison to bare iridium and platinum catalysts. To get insight into the reaction dynamics and mechanisms, such electrochemical diagnostic techniques as cyclic voltammetry and rotating ring-disk electrode voltammetry have been considered. To mimic operation of catalysts in real fuel cells, additional experiments utilizing gas diffusion electrode have also been performed. Materials are subjected to surface analytical, structural and microscopic characterization using X-ray photoelectron (XPS), fluorescence (EDX), and diffraction (XRD) methods as well as transmission and scanning electron microscopies. At low (optimum) coverages of selenium on surfaces of iridium nanoparticles, the reduction of oxygen tends to proceed at more positive potentials in comparison to bare iridium under analogous conditions. Apparently, strong affinity of bare iridium to form oxo groups on its surface (known as inhibiting oxygen reduction) is largely suppressed in presence of selenium or nitrogen atoms. But the optimum selenium-modified iridium system produces somewhat higher amounts of the hydrogen peroxide intermediate presumably due to partial physical blocking of iridium (metal and metal oxo) sites (that would otherwise be active toward the reduction of the H2O2 intermediate). High tolerance (during reduction of oxygen) of the optimum Ir-based catalyst (functionalized using selenourea) to the parasitic (e.g. in polymer membrane fuel cells) simultaneous oxidation of organic fuels (e.g. methanol or ethanol) should be mentioned as well.
Robo2 is the cell surface receptor for the repulsive guidance cue Slit and is involved in axon guidance and neuronal migration. Nephrin is a podocyte slit-diaphragm protein that functions in the ...kidney glomerular filtration barrier. Here, we report that Robo2 is expressed at the basal surface of mouse podocytes and colocalizes with nephrin. Biochemical studies indicate that Robo2 forms a complex with nephrin in the kidney through adaptor protein Nck. In contrast to the role of nephrin that promotes actin polymerization, Slit2-Robo2 signaling inhibits nephrin-induced actin polymerization. In addition, the amount of F-actin associated with nephrin is increased in Robo2 knockout mice that develop an altered podocyte foot process structure. Genetic interaction study further reveals that loss of Robo2 alleviates the abnormal podocyte structural phenotype in nephrin null mice. These results suggest that Robo2 signaling acts as a negative regulator on nephrin to influence podocyte foot process architecture.
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► Robo2 colocalizes with nephrin in kidney podocytes ► Robo2 forms a complex with nephrin through the Nck protein ► Slit2-Robo2 signaling inhibits nephrin-induced actin polymerization ► Robo2 loss alleviates podocyte structural phenotype in nephrin mutant mice
The unique interdigitating foot processes of kidney podocytes, together with intervening slit diaphragms, confer selective permeability to the glomerular filtration barrier. Nephrin, a major slit-diaphragm component, regulates permeability and promotes actin polymerization. Lu and colleagues now identify the neuronal guidance cue receptor Robo2 as a podocyte protein that forms a complex with nephrin through the adaptor protein Nck. Their study suggests that Robo2 signaling acts as a negative regulator of nephrin-induced actin polymerization, thereby modulating podocyte foot process structure.
Pregnancy exerts profound impact on female immune system. The first signs of pregnancy recognition by immune system are observed even before implantation. The most visible effects are present in the ...local compartment, i.e. in uterine draining lymph nodes and the decidua, while peripheral changes are less obvious. In our recent paper we indicated that costimulation phenotype of APCs in spleens of female mice during the preimplantation period of pregnancy differs from mice in pseudopregnancy. However, the effect of differential costimulation in the context of the T lymphocyte function at periphery in early pregnancy is still unknown. For that reason, we decided to investigate global protein expression in splenic CD4(+) lymphocytes in order to identify and validate the most important biomarkers characteristic for the preimplantation period of pregnancy at periphery. Two-dimensional electrophoresis (2-DE) and mass spectrometry (MS) were utilized to analyze the protein expression pattern of magnetically sorted CD4(+) lymphocytes from spleens of pregnant and pseudopregnant females at 3.5 days after mating. The first goal of this study was to create a 2-DE map of the splenic CD4(+) T cells of pregnant mice. As a result, 106 protein spots from 373 were identified using MS. The comparison of lymphocyte protein patterns between pregnant and pseudopregnant mice depicted differential expression of 11 identified proteins belonging to the group of proteins involved in cytoskeletal structure, cell motility and metabolism. Profoundly diminished expression of cofilin-1, F-actin capping protein subunit alpha and malate dehydrogenase proteins in lymphocytes of pregnant mice indicates that preimplantation pregnancy could change the activation state of peripheral CD4(+) lymphocytes.
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