Faculty Bibliography

OBJECTIVE: We hypothesized that the hypoxia-inducible factor (HIF) 1alpha in vascular smooth muscle contributes to the development of atherosclerosis, and links intravascular pressure to this process. APPROACH AND RESULTS: Transverse aortic constriction was used to create high-pressure vascular segments in control, apolipoprotein E (ApoE)-/-, smooth muscle-HIF1alpha-/-, and ApoE-/-xsmooth muscle-HIF1alpha-/- double-knockout mice. Transverse aortic constriction selectively induced atherosclerosis in high-pressure vascular segments in young ApoE-/- mice on normal chow, including coronary plaques within 1 month. Concomitant deletion of HIF1alpha from smooth muscle significantly reduced vascular inflammation, and attenuated atherosclerosis. CONCLUSIONS: HIF1alpha in vascular smooth muscle plays an important role in the pathogenesis of atherosclerosis, and may provide a mechanistic link between blood pressure, vascular inflammation, and lipid deposition.

Brain-derived neurotrophic factor (BDNF) plays an important role in neurodevelopment, synaptic plasticity, learning and memory, and in preventing neurodegeneration. Despite decades of investigations into downstream signaling cascades and changes in cellular processes, the mechanisms of how BDNF reshapes circuits in vivo remain unclear. This informational gap partly arises from the fact that the bulk of studies into the molecular actions of BDNF have been performed in dissociated neuronal cultures, while the majority of studies on synaptic plasticity, learning and memory were performed in acute brain slices or in vivo. A recent study by Bowling-Bhattacharya et al., measured the proteomic changes in acute adult hippocampal slices following treatment and reported changes in proteins of neuronal and non-neuronal origin that may in concert modulate synaptic release and secretion in the slice. In this paper, we place these findings into the context of existing literature and discuss how they impact our understanding of how BDNF can reshape the brain.

Birds have a distally reduced, splinter-like fibula that is shorter than the tibia. In embryonic development, both skeletal elements start out with similar lengths. We examined molecular markers of cartilage differentiation in chicken embryos. We found that the distal end of the fibula expresses Indian hedgehog (IHH), undergoing terminal cartilage differentiation, and almost no Parathyroid-related protein (PTHrP), which is required to develop a proliferative growth plate (epiphysis). Reduction of the distal fibula may be influenced earlier by its close contact with the nearby fibulare, which strongly expresses PTHrP. The epiphysis-like fibulare however then separates from the fibula, which fails to maintain a distal growth plate, and fibular reduction ensues. Experimental downregulation of IHH signaling at a postmorphogenetic stage led to a tibia and fibula of equal length: The fibula is longer than in controls and fused to the fibulare, whereas the tibia is shorter and bent. We propose that the presence of a distal fibular epiphysis may constrain greater growth in the tibia. Accordingly, many Mesozoic birds show a fibula that has lost its distal epiphysis, but remains almost as long as the tibia, suggesting that loss of the fibulare preceded and allowed subsequent evolution of great fibulo-tibial disparity.

INTRODUCTION/BACKGROUND:Insulin resistance and type 2 diabetes mellitus (T2D) are associated with increased risk for cognitive impairment, Alzheimer's disease (AD) and vascular dementia. SORCS1 encodes a protein-sorting molecule genetically linked to both T2D and AD. The association of SORCS1 with both AD and T2D is sexually dimorphic in humans, with both disease associations showing more robust effects in females. Based on published evidence that manipulation of the mouse genome combining multiple genes related to cerebral amyloidosis, to T2D, or both, might provide novel mouse models with exacerbated amyloid and/or diabetes phenotypes, we assessed memory, glucose homeostasis, and brain biochemistry and pathology in male and female wild-type, Sorcs1 -/-, APP/PSEN1, and Sorcs1 -/- X APP/PSEN1 mice. RESULTS:Male mice with either the APP/PSEN1 or Sorcs1 -/- genotype displayed earlier onset and persistent impairment in both learning behavior and glucose homeostasis. Unlike prior examples in the literature, the behavioral and metabolic abnormalities in male mice were not significantly exacerbated when the two disease model mice (Sorcs1 -/- models T2D; APP/PSEN1 models AD) were crossed. However, female Sorcs1 -/- X APP/PSEN1 mice exhibited worse metabolic dysfunction than Sorcs1 -/- knockout mice and worse memory than wild-type mice. The deletion of Sorcs1 from APP/PSEN1 mutant mice led to no obvious changes in brain levels of total or oligomeric amyloid-beta (Aβ) peptide. CONCLUSIONS:In general, unexpectedly, there was a trend for gene targeting of Sorcs1-/- to partially mitigate, not exacerbate, the metabolic and amyloid pathologies. These results indicate that crossing AD model mice and T2D model mice may not always cause exacerbation of both the amyloidosis phenotype and the metabolic phenotype and highlight the unexpected pitfalls of creating mixed models of disease.

Oxytocin is a neuropeptide important for social behaviors such as maternal care and parent-infant bonding. It is believed that oxytocin receptor signaling in the brain is critical for these behaviors, but it is unknown precisely when and where oxytocin receptors are expressed or which neural circuits are directly sensitive to oxytocin. To overcome this challenge, we generated specific antibodies to the mouse oxytocin receptor and examined receptor expression throughout the brain. We identified a distributed network of female mouse brain regions for maternal behaviors that are especially enriched for oxytocin receptors, including the piriform cortex, the left auditory cortex, and CA2 of the hippocampus. Electron microscopic analysis of the cerebral cortex revealed that oxytocin receptors were mainly expressed at synapses, as well as on axons and glial processes. Functionally, oxytocin transiently reduced synaptic inhibition in multiple brain regions and enabled long-term synaptic plasticity in the auditory cortex. Thus modulation of inhibition may be a general mechanism by which oxytocin can act throughout the brain to regulate parental behaviors and social cognition. SIGNIFICANCE STATEMENT: Oxytocin is an important peptide hormone involved in maternal behavior and social cognition, but it has been unclear what elements of neural circuits express oxytocin receptors due to the paucity of suitable antibodies. Here, we developed new antibodies to the mouse oxytocin receptor. Oxytocin receptors were found in discrete brain regions and at cortical synapses for modulating excitatory-inhibitory balance and plasticity. These antibodies should be useful for future studies of oxytocin and social behavior.

Animals must decide when to consume precious fat stores in order to sustain life. In this issue of Cell Reports, Witham et al. report how oxygen-sensing neurons ensure this decision is made under environmental conditions that favor metabolic efficiency.

Progranulin (PGRN), a pleiotrophic growth factor, is known to play an important role in the maintenance and regulation of the homeostatic dynamics of normal tissue development, proliferation, regeneration, and host-defense. PGRN also has potent anti-inflammatory functionality, and deregulated PGRN is associated with rheumatoid arthritis and inflammatory bowel disease. We have previously reported that PGRN directly binds to TNFR and significantly enhances Treg population and stimulatesIL-10 production. To further investigate PGRN's function in the immune system we performed a gene array analysis on CD4+ T cells from wild type B6 mice and PGRN -/- mice. We identified many chemokines and their receptors, among which CXCL9 and CXCL10 were most prominent, that were significantly induced in PGRN null mice. Administration of recombinant PGRN protein strongly inhibited TNF and IFN-gamma-induced CXCL9 and CXCL10 expression. In addition, CXCL9 expression is strongly upregulated in PGRN KO mice and its level is correlated with severity of inflammation in a dermatitis model. Further, we have demonstrated that PGRN-mediated inhibition of chemokine expression largely depends on TNFR1. Taken together, this study provides new insights into the mechanisms underlying PGRN mediated regulation of various inflammatory and autoimmune diseases.

Atherosclerosis and its attendant clinical complications, such as myocardial infarction, stroke, and peripheral artery disease, are the leading cause of morbidity and mortality in Western societies. In response to biochemical and biomechanical stimuli, atherosclerotic lesion formation occurs from the participation of a range of cell types, inflammatory mediators, and shear stress. Over the past decade, microRNAs (miRNAs) have emerged as evolutionarily conserved, noncoding small RNAs that serve as important regulators and fine-tuners of a range of pathophysiological cellular effects and molecular signaling pathways involved in atherosclerosis. Accumulating studies reveal the importance of miRNAs in regulating key signaling and lipid homeostasis pathways that alter the balance of atherosclerotic plaque progression and regression. In this review, we highlight current paradigms of miRNA-mediated effects in atherosclerosis progression and regression. We provide an update on the potential use of miRNAs diagnostically for detecting increasing severity of coronary disease and clinical events. Finally, we provide a perspective on therapeutic opportunities and challenges for miRNA delivery in the field.