Jagged1 is altered in alzheimer’s disease and regulates spatial memory processing

Notch signaling plays an instrumental role in hippocampus-dependent memory formation and recent evidence indicates a displacement of Notch1 and a reduction its activity in hippocampal and cortical neurons from Alzheimer's disease (AD) patients. As Notch activation depends on ligand availability, we investigated whether Jagged1 expression was altered in brain specimen of AD patients. We found that Jagged1 expression was reduced in the CA fields and that there was a gradual reduction of Jagged1 in the cerebrospinal fluid (CSF) with the progression of dementia. Given the role of Notch signaling in memory encoding, we investigated whether targeted loss of Jagged1 in neurons may be responsible for the memory loss seen in AD patients. Using a transgenic mouse model, we show that the targeted loss of Jagged1 expression during adulthood is sufficient to cause spatial memory loss and a reduction in exploration-dependent Notch activation. We also show that Jagged1 is selectively enriched at the presynaptic terminals in mice. Overall, the present data emphasizes the role of the Notch ligand, Jagged1, in memory formation and the potential deficit of the signaling ligand in AD patients

Progressive signaling changes in the olfactory nerve of patients with Alzheimer’s disease

Olfaction declines with aging and appears to be a prodromal sign of cognitive decline in progressive neurodegenerative diseases. Nevertheless, very little is known about the pathophysiological changes underlying smell loss that may reflect early network dysfunction. A cross-sectional histoanatomical study was conducted on postmortem olfactory nerves of patients with increasing severity of dementia from mild cognitive impairment (MCI) to moderate and severe Alzheimer's disease. The olfactory bulbs and tracts show a prominent and progressive tauopathy in contrast to a weaker amyloid pathology localized to the glomerular region. Topological analysis of Notch signaling components reveals a transient increase in Jagged1 expression in mitral cells of the olfactory bulb of patients with MCI and a gradual decline onwards. Analysis of the olfactory tract reveals an abundance of corpora amylacea, which declines starting from the MCI stage. With the increasing severity of dementia, corpora amylacea are characterized by a gradual shift in cytoskeletal proteins, tau, MAP2 and glial fibrillary acid protein, as well as by a decrease in their Reelin and Jagged1 content. Our research indicates that the olfactory nerve undergoes early and sequential morphological and signaling alterations that correlate with the development of dementia suggesting that this structure may capture and propagate neuronal network imbalances to connected higher brain centers of the entorhinal cortex and hippocampus

DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport.

The small intestine is a dynamic and complex organ that is characterized by constant epithelium turnover and crosstalk among various cell types and the microbiota. Lymphatic capillaries of the small intestine, called lacteals, play key roles in dietary fat absorption and the gut immune response; however, little is known about the molecular regulation of lacteal function. Here, we performed a high-resolution analysis of the small intestinal stroma and determined that lacteals reside in a permanent regenerative, proliferative state that is distinct from embryonic lymphangiogenesis or quiescent lymphatic vessels observed in other tissues. We further demonstrated that this continuous regeneration process is mediated by Notch signaling and that the expression of the Notch ligand delta-like 4 (DLL4) in lacteals requires activation of VEGFR3 and VEGFR2. Moreover, genetic inactivation of Dll4 in lymphatic endothelial cells led to lacteal regression and impaired dietary fat uptake. We propose that such a slow lymphatic regeneration mode is necessary to match a unique need of intestinal lymphatic vessels for both continuous maintenance, due to the constant exposure to dietary fat and mechanical strain, and efficient uptake of fat and immune cells. Our work reveals how lymphatic vessel responses are shaped by tissue specialization and uncover a role for continuous DLL4 signaling in the function of adult lymphatic vasculature

FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature.

Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease

Minor intron splicing is critical for survival of lethal prostate cancer.

The evolutionarily conserved minor spliceosome (MiS) is required for protein expression of ∼714 minor intron-containing genes (MIGs) crucial for cell-cycle regulation, DNA repair, and MAP-kinase signaling. We explored the role of MIGs and MiS in cancer, taking prostate cancer (PCa) as an exemplar. Both androgen receptor signaling and elevated levels of U6atac, a MiS small nuclear RNA, regulate MiS activity, which is highest in advanced metastatic PCa. siU6atac-mediated MiS inhibition in PCa in vitro model systems resulted in aberrant minor intron splicing leading to cell-cycle G1 arrest. Small interfering RNA knocking down U6atac was ∼50% more efficient in lowering tumor burden in models of advanced therapy-resistant PCa compared with standard antiandrogen therapy. In lethal PCa, siU6atac disrupted the splicing of a crucial lineage dependency factor, the RE1-silencing factor (REST). Taken together, we have nominated MiS as a vulnerability for lethal PCa and potentially other cancers

DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport

The small intestine is a dynamic and complex organ that is characterized by constant epithelium turnover and crosstalk among various cell types and the microbiota. Lymphatic capillaries of the small intestine, called lacteals, play key roles in dietary fat absorption and the gut immune response; however, little is known about the molecular regulation of lacteal function. Here, we performed a high-resolution analysis of the small intestinal stroma and determined that lacteals reside in a permanent regenerative, proliferative state that is distinct from embryonic lymphangiogenesis or quiescent lymphatic vessels observed in other tissues. We further demonstrated that this continuous regeneration process is mediated by Notch signaling and that the expression of the Notch ligand delta-like 4 (DLL4) in lacteals requires activation of VEGFR3 and VEGFR2. Moreover, genetic inactivation of Dll4 in lymphatic endothelial cells led to lacteal regression and impaired dietary fat uptake. We propose that such a slow lymphatic regeneration mode is necessary to match a unique need of intestinal lymphatic vessels for both continuous maintenance, due to the constant exposure to dietary fat and mechanical strain, and efficient uptake of fat and immune cells. Our work reveals how lymphatic vessel responses are shaped by tissue specialization and uncover a role for continuous DLL4 signaling in the function of adult lymphatic vasculature

FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1

The mechanisms of blood vessel maturation into distinct parts of the blood vasculature such as arteries, veins, and capillaries have been the subject of intense investigation over recent years. In contrast, our knowledge of lymphatic vessel maturation is still fragmentary. In this study, we provide a molecular and morphological characterization of the major steps in the maturation of the primary lymphatic capillary plexus into collecting lymphatic vessels during development and show that forkhead transcription factor Foxc2 controls this process. We further identify transcription factor NFATc1 as a novel regulator of lymphatic development and describe a previously unsuspected link between NFATc1 and Foxc2 in the regulation of lymphatic maturation. We also provide a genome-wide map of FOXC2-binding sites in lymphatic endothelial cells, identify a novel consensus FOXC2 sequence, and show that NFATc1 physically interacts with FOXC2-binding enhancers. As damage to collecting vessels is a major cause of lymphatic dysfunction in humans, our results suggest that FOXC2 and NFATc1 are potential targets for therapeutic intervention

Lentiviral-mediated gene transfer of brain-derived neurotrophic factor is neuroprotective in a mouse model of neonatal excitotoxic challenge

Excitotoxicity may be a critical factor in the formation of brain lesions associated with cerebral palsy. When injected into the murine neopallium at postnatal day 5, the glutamatergic analog N-methyl-D-aspartate (NMDA) produces transcortical neuronal death and periventricular white matter cysts, which mimic brain damage observed in human term and preterm neonates at risk for developing cerebral palsy. We previously showed that intracerebral injection of brain-derived neurotrophic factor (BDNF) was neuroprotective in this model. Because BDNF does not easily cross the blood-brain barrier, alternative strategies to avoid repeated intracerebral injections of BDNF should be tested, particularly when the goal of such translational research is ultimately to achieve clinical application. The goal of the present study was to assess the protective role of lentiviral-mediated gene transfer of BDNF against excitotoxic lesions induced by NMDA in newborn mice. We first assessed the biological activity of BDNF gene transfer in vitro and determined the efficiency of gene transfer in our in vivo model. We next administered the BDNF-expressing vector by intracerebral injection in neonatal mice, 3 days before inducing NMDA lesions. When compared with a control green fluorescent protein-expressing lentiviral vector, administration of BDNF-expressing vector induced a significant protection of the periventricular white matter and cortical plate against the NMDA-mediated insult. Intraventricular delivery of the BDNF-expressing lentiviral vector was more efficient in terms of neuroprotection than the intraparenchymal route. Altogether, the present study shows that viral-mediated gene transfer of BDNF to newborn mouse brain is feasible and affords significant neuroprotection against an excitotoxic insult

Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice

Recent data suggest that the gut microbiota plays a significant role in fat accumulation. However, it is not clear whether gut microbiota is involved in the pathophysiology of type 2 diabetes. To assess this issue, we modulated gut microbiota via antibiotics administration in two different mouse models with insulin resistance. Results from dose-determination studies showed that a combination of norfloxacin and ampicillin, at a dose of 1 g/L, maximally suppressed the numbers of cecal aerobic and anaerobic bacteria in ob/ob mice. After a 2-wk intervention with the antibiotic combination, both ob/ob and diet-induced obese and insulin-resistant mice showed a significant improvement in fasting glycemia and oral glucose tolerance. The improved glycemic control was independent of food intake or adiposity because pair-fed ob/ob mice were as glucose intolerant as the control ob/ob mice. Reduced liver triglycerides and increased liver glycogen correlated with improved glucose tolerance in the treated mice. Concomitant reduction of plasma lipopolysaccharides and increase of adiponectin further supported the antidiabetic effects of the antibiotic treatment in ob/ob mice. In summary, modulation of gut microbiota ameliorated glucose tolerance of mice by altering the expression of hepatic and intestinal genes involved in inflammation and metabolism, and by changing the hormonal, inflammatory, and metabolic status of the host