Emmette R. Hutchison

miR-130 Suppresses Adipogenesis by Inhibiting Peroxisome Proliferator-Activated Receptor Expression

ABSTRACT Adipose tissue development is tightly regulated by altering gene expression. MicroRNAs are strong posttranscriptional regulators of mammalian differentiation. We hypothesized that microRNAs might influence human adipogenesis by targeting specific adipogenic factors. We identified microRNAs that showed varying abundance during the differentiation of human preadipocytes into adipocytes. Among them, miR-130 strongly affected adipocyte differentiation, as overexpressing miR-130 impaired adipogenesis and reducing miR-130 enhanced adipogenesis. A key effector of miR-130 actions was the protein peroxisome proliferator-activated receptor γ (PPARγ), a major regulator of adipogenesis. Interestingly, miR-130 potently repressed PPARγ expression by targeting both the PPARγ mRNA coding and 3′ untranslated regions. Adipose tissue from obese women contained significantly lower miR-130 and higher PPARγ mRNA levels than that from nonobese women. Our findings reveal that miR-130 reduces adipogenesis by repressing PPARγ biosynthesis and suggest that perturbations in this regulation is linked to human obesity.

Evidence for miR-181 involvement in neuroinflammatory responses of astrocytes.

Inflammation is a common component of acute injuries of the central nervous system (CNS) such as ischemia, and degenerative disorders such as Alzheimers disease. Glial cells play important roles in local CNS inflammation, and an understanding of the roles for microRNAs in glial reactivity in injury and disease settings may therefore lead to the development of novel therapeutic interventions. Here, we show that the miR‐181 family is developmentally regulated and present in high amounts in astrocytes compared to neurons. Overexpression of miR‐181c in cultured astrocytes results in increased cell death when exposed to lipopolysaccharide (LPS). We show that miR‐181 expression is altered by exposure to LPS, a model of inflammation, in both wild‐type and transgenic mice lacking both receptors for the inflammatory cytokine TNF‐α. Knockdown of miR‐181 enhanced LPS‐induced production of pro‐inflammatory cytokines (TNF‐α, IL‐6, IL‐1β, IL‐8) and HMGB1, while overexpression of miR‐181 resulted in a significant increase in the expression of the anti‐inflammatory cytokine IL‐10. To assess the effects of miR‐181 on the astrocyte transcriptome, we performed gene array and pathway analysis on astrocytes with reduced levels of miR‐181b/c. To examine the pool of potential miR‐181 targets, we employed a biotin pull‐down of miR‐181c and gene array analysis. We validated the mRNAs encoding MeCP2 and X‐linked inhibitor of apoptosis as targets of miR‐181. These findings suggest that miR‐181 plays important roles in the molecular responses of astrocytes in inflammatory settings. Further understanding of the role of miR‐181 in inflammatory events and CNS injury could lead to novel approaches for the treatment of CNS disorders with an inflammatory component.

An event-related fMRI investigation of phonological–lexical competition

This study explored the neural correlates of phonological-lexical competition and frequency on word recognition. An event-related fMRI experiment was conducted using an auditory lexical decision task in which word and nonword stimuli varied in terms of neighborhood density (high and low). Word stimuli also varied in terms of frequency (high and low). Behavioral results were similar to those of Luce and Pisoni [Luce, P. A., & Pisoni, D. B. (1998). Recognizing spoken words: The neighborhood activation model. Ear and Hearing, 19, 1-36], with the reaction time data showing a main effect of word frequency and density as well as a significant interaction effect between these two factors. fMRI results revealed an overall greater neural response for high-density compared to low-density words in the left supramarginal gyrus, consistent with the view that there are greater demands on phonological processing under conditions of increased phonological-lexical competition. The comparison between high and low frequency words revealed greater activation for high frequency words in both anterior and posterior left middle temporal gyrus. A significant interaction between density and frequency was found in lateral and medial frontal structures. This frontal activation may reflect the greater computational resources required in integrating frequency and density information in order to access a word. Overall, these findings demonstrate the sensitivity of neural structures to different properties of the lexicon.

miR-375 Inhibits Differentiation of Neurites by Lowering HuD Levels

ABSTRACT Neuronal development and plasticity are maintained by tightly regulated gene expression programs. Here, we report that the developmentally regulated microRNA miR-375 affects dendrite formation and maintenance. miR-375 overexpression in mouse hippocampus potently reduced dendrite density. We identified the predominantly neuronal RNA-binding protein HuD as a key effector of miR-375 influence on dendrite maintenance. Heterologous reporter analysis verified that miR-375 repressed HuD expression through a specific, evolutionarily conserved site on the HuD 3′ untranslated region. miR-375 overexpression lowered both HuD mRNA stability and translation and recapitulated the effects of HuD silencing, which reduced the levels of target proteins with key functions in neuronal signaling and cytoskeleton organization (N-cadherin, PSD-95, RhoA, NCAM1, and integrin α1). Moreover, the increase in neurite outgrowth after brain-derived neurotrophic factor (BDNF) treatment was diminished by miR-375 overexpression; this effect was rescued by reexpression of miR-375-refractory HuD. Our findings indicate that miR-375 modulates neuronal HuD expression and function, in turn affecting dendrite abundance.

TLR2 Activation Inhibits Embryonic Neural Progenitor Cell Proliferation

J. Neurochem. (2010) 114, 462–474.

Recruitment of Anterior and Posterior Structures in Lexical-Semantic Processing: An fMRI Study Comparing Implicit and Explicit Tasks

Previous studies examining explicit semantic processing have consistently shown activation of the left inferior frontal gyrus (IFG). In contrast, implicit semantic processing tasks have shown activation in posterior areas including the superior temporal gyrus (STG) and the middle temporal gyrus (MTG) with less consistent activation in the IFG. These results raise the question whether the functional role of the IFG is related to those processes needed to make a semantic decision or to processes involved in the extraction and analysis of meaning. This study examined neural activation patterns during a semantic judgment task requiring overt semantic analysis, and then compared these activation patterns to previously obtained results using the same semantically related and unrelated word pairs in a lexical decision task which required only implicit semantic processing (Rissman, J., Eliassen, J. C., & Blumstein, S. E. (2003). An event-related fMRI investigation of implicit semantic priming. Journal of Cognitive Neuroscience, 15, 1160-1175). The behavioral results demonstrated that the tasks were equivalent in difficulty. fMRI results indicated that the IFG and STG bilaterally showed greater activation for semantically unrelated than related word pairs across the two tasks. Comparison of the two task types across conditions revealed greater activation for the semantic judgment task only in the STG bilaterally and not in the IFG. These results suggest that the pre-frontal cortex is recruited similarly in the service of both the lexical decision and semantic judgment tasks. The increased activation in the STG in the semantic judgment task reflects the greater depth of semantic processing required in this task and indicates that the STG is not simply a passive store of lexical-semantic information but is involved in the active retrieval of this information.

Telomere shortening in neurological disorders: an abundance of unanswered questions

Telomeres, ribonucleoprotein complexes that cap eukaryotic chromosomes, typically shorten in leukocytes with aging. Aging is a primary risk factor for neurodegenerative disease (ND), and a common assumption has arisen that leukocyte telomere length (LTL) can serve as a predictor of neurological disease. However, the evidence for shorter LTL in Alzheimers and Parkinsons patients is inconsistent. The diverse causes of telomere shortening may explain variability in LTL between studies and individuals. Additional research is needed to determine whether neuronal and glial telomeres shorten during aging and in neurodegenerative disorders, if and how LTL is related to brain cell telomere shortening, and whether telomere shortening plays a causal role in or exacerbates neurological disorders.

Functional MRI and Response Inhibition in Children Exposed to Cocaine in utero: Preliminary Findings

This study investigated the potential long-term effects of cocaine exposure on brain functioning using fMRI in school-aged children. The sample included 12 children with prenatal cocaine exposure and 12 non-exposed children (8–9 years old). Groups did not differ on IQ, socioeconomic status, or perinatal risk factors. A response inhibition task was administered during an fMRI scan using a 1.5-T MRI system. Task performance did not differentiate groups, but groups were differentiated by patterns of task-related brain activity. Cocaine-exposed children showed greater activation in the right inferior frontal cortex and caudate during response inhibition, whereas non-exposed children showed greater activations in temporal and occipital regions. These preliminary findings suggest that prenatal cocaine may affect the development of brain systems involved in the regulation of attention and response inhibition.

The Therapeutic Potential of microRNAs in Nervous System Damage, Degeneration, and Repair

MicroRNAS (miRNAs) have been suggested to play important roles in the central nervous system during development as well as disease. miRNAs appear to be dysregulated in a number of neurodegenerative diseases, developmental disorders, and as a result of stroke. Each miRNA has the ability to regulate hundreds of messenger RNA transcripts, both by causing degradation of the mRNA and by inhibition of protein translation. Recent findings suggest that it may eventually be possible to treat some neurological disorders by restoring or inhibiting miRNAs altered by disease pathology. Both viral delivery and administration of modified oligonucleotides mimicking or inhibiting specific miRNAs have been effective in model systems. Artificial miRNAs have also been generated for the repression of specific transcripts. Alteration of miRNA expression by disease and insult also holds the potential for improved diagnostic tools. Finally, miRNAs have been shown to control cellular proliferation and specification, suggesting that manipulation of miRNAs in cultured cells could result in more convenient generation of pure cell populations for transplantation.

Interrogation of brain miRNA and mRNA expression profiles reveals a molecular regulatory network that is perturbed by mutant huntingtin.

Emerging evidence indicates that microRNAs (miRNAs) may play an important role in the pathogenesis of Huntingtons disease (HD). To identify the individual miRNAs that are altered in HD and may therefore regulate a gene network underlying mutant huntingtin‐induced neuronal dysfunction in HD, we performed miRNA array analysis combined with mRNA profiling in the cerebral cortex from N171‐82Q HD mice. Expression profiles of miRNAs as well as mRNAs in HD mouse cerebral cortex were analyzed and confirmed at different stages of disease progression; the most significant changes of miRNAs in the cerebral cortex were also detected in the striatum of HD mice. Our results revealed a significant alteration of miR‐200 family members, miR‐200a, and miR‐200c in the cerebral cortex and the striatum, at the early stage of disease progression in N171‐82Q HD mice. We used a coordinated approach to integrate miRNA and mRNA profiling, and applied bioinformatics to predict a target gene network potentially regulated by these significantly altered miRNAs that might be involved in HD disease progression. Interestingly, miR‐200a and miR‐200c are predicted to target genes regulating synaptic function, neurodevelopment, and neuronal survival. Our results suggest that altered expression of miR‐200a and miR‐200c may interrupt the production of proteins involved in neuronal plasticity and survival, and further investigation of the involvement of perturbed miRNA expression in HD pathogenesis is warranted, and may lead to reveal novel approaches for HD therapy.