EPAC Null Mutation Impairs Learning and Social Interactions via Aberrant Regulation of miR-124 and Zif268 Translation

Yang, Ying; Shu, Xuefeng; Liú, Dan; Shang, You; Wu, Yan; Pei, Lei; Xu, Xin; Tian, Qing; Zhang, Jian; Qian, Kun; Wang, Yaxian; Petralia, Ronald S.; Tu, Weihong; Zhu, Ling‐Qiang; Wang, Jian‐Zhi; Lu, Youming

doi:10.1016/j.neuron.2012.02.003

Cited by 163 publications

(184 citation statements)

References 58 publications

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“…In addition to its role in neuronal differentiation, miR-124 regulates neuronal maturation by targeting the expression of cAMP response element-binding protein (CREB) (Rajasethupathy et al, 2009), LIM/homeobox protein 2 (Lhx2) (Sanuki et al, 2011), Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) (Gu et al, 2014), and the small GTPase Ras homolog growthrelated (RhoG) (Franke et al, 2012). Recently, miR-124 was shown to regulate synaptic transmission and cognition by inhibiting the expression of early growth response gene 1 (Egr1) Yang et al, 2012).…”

Section: Mirnas In Neurodevelopmentmentioning

confidence: 99%

MicroRNAs: Small molecules with big roles in neurodevelopment and diseases

Sun

Shi

2015

Experimental Neurology

164

107

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MicroRNAs (miRNAs) are single-stranded, non-coding RNA molecules that play important roles in the development and functions of the brain. Extensive studies have revealed critical roles for miRNAs in brain development and function. Dysregulation or altered expression of miRNAs is associated with abnormal brain development and pathogenesis of neurodevelopmental diseases. This review serves to highlight the versatile roles of these small RNA molecules in normal brain development and their association with neurodevelopmental disorders, in particular, two closely related neuropsychiatric disorders of neurodevelopmental origin, schizophrenia and bipolar disorder.

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Section: Mirnas In Neurodevelopmentmentioning

confidence: 99%

MicroRNAs: Small molecules with big roles in neurodevelopment and diseases

Sun

Shi

2015

Experimental Neurology

164

107

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“…Conversely, overexpression of miR-124 mimics the behavioural and electrophysiological phenotype of EPAC-deficient mice [66]. The effect most probably is mediated through inadequate EPAC-Rap1 regulation on miR-124 levels which in turn represses translation of Zif268 [66]. The function of miR-124 in memory formation appears to be highly conserved, because miR-124 also regulates synaptic facilitation and memory formation in Aplysia californica [67].…”

Section: (I) Mir-132mentioning

confidence: 99%

MicroRNAs and synaptic plasticity—a mutual relationship

Aksoy‐Aksel

Zampa

Schratt

2014

Phil. Trans. R. Soc. B

105

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MicroRNAs (miRNAs) are rapidly emerging as central regulators of gene expression in the postnatal mammalian brain. Initial studies mostly focused on the function of specific miRNAs during the development of neuronal connectivity in culture, using classical gain-and loss-of-function approaches. More recently, first examples have documented important roles of miRNAs in plastic processes in intact neural circuits in the rodent brain related to higher cognitive abilities and neuropsychiatric disease. At the same time, evidence is accumulating that miRNA function itself is subjected to sophisticated control mechanisms engaged by the activity of neural circuits. In this review, we attempt to pay tribute to this mutual relationship between miRNAs and synaptic plasticity. In particular, in the first part, we summarize how neuronal activity influences each step in the lifetime of miRNAs, including the regulation of transcription, maturation, gene regulatory function and turnover in mammals. In the second part, we discuss recent examples of miRNA function in synaptic plasticity in rodent models and their implications for higher cognitive function and neurological disorders, with a special emphasis on epilepsy as a disorder of abnormal nerve cell activity.

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“…In addition, a series of recent studies demonstrated that 8-CPT-conjugated cAMP analogs and their metabolites can exert diverse biological functions via cAMP-independent mechanisms (39)(40)(41)(42). Over the last few years, several studies involving the use of Epac2 or Epac1/2 double knockout mice have been published (43)(44)(45). A recent study showed that double knockout of Epac1 and Epac2 in the forebrain of mice disrupts spatial learning and social interactions via upregulation of miR-124 transcription (44).…”

Section: Fig 6 Epac1mentioning

confidence: 99%

“…Over the last few years, several studies involving the use of Epac2 or Epac1/2 double knockout mice have been published (43)(44)(45). A recent study showed that double knockout of Epac1 and Epac2 in the forebrain of mice disrupts spatial learning and social interactions via upregulation of miR-124 transcription (44). Epac2 Ϫ/Ϫ knockout mice had no significant differences in plasma insulin and blood glucose levels versus wild-type mice in response to a glucose challenge.…”

Section: Fig 6 Epac1mentioning

confidence: 99%

Enhanced Leptin Sensitivity, Reduced Adiposity, and Improved Glucose Homeostasis in Mice Lacking Exchange Protein Directly Activated by Cyclic AMP Isoform 1

Yan

Mei

Cheng

et al. 2013

Molecular and Cellular Biology

100

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The prototypic second messenger cyclic AMP (cAMP) is essential for controlling cellular metabolism, including glucose and lipid homeostasis. In mammals, the majority of cAMP functions are mediated by cAMP-dependent protein kinase (PKA) and exchange proteins directly activated by cAMP (Epacs). To explore the physiological functions of Epac1, we generated Epac1 knockout mice. Here we report that Epac1 null mutants have reduced white adipose tissue and reduced plasma leptin levels but display heightened leptin sensitivity. Epac1-deficient mice are more resistant to high-fat diet-induced obesity, hyperleptinemia, and glucose intolerance. Furthermore, pharmacological inhibition of Epac by use of an Epac-specific inhibitor reduces plasma leptin levels in vivo and enhances leptin signaling in organotypic hypothalamic slices. Taken together, our results demonstrate that Epac1 plays an important role in regulating adiposity and energy balance. Obesity is a grave health problem, as it is closely related to the leading causes of morbidity and mortality, such as cardiovascular diseases, type 2 diabetes, hypertension, depression, and cancer (1). Over the last 2 decades, obesity has reached epidemic proportions in the United States: more than 35% of adults in the United States are obese, and more than two-thirds are overweight (2). Furthermore, 500 million people worldwide are obese, representing approximately 12% of the adult population on earth (3). Chronic excessive food/energy intake, mediated by leptin resistance, is a major factor contributing to obesity. To date, few effective treatment options are available for obesity (4). Therefore, a better understanding of the underlying molecular mechanisms of obesity development and effective, safe therapeutic interventions are urgently needed. Cyclic AMP (cAMP)-mediated signaling pathways are important for maintaining metabolic homeostasis and have been implicated in regulating leptin production and secretion (5-7). In mammals, the majority of cAMP functions are mediated by cAMP-dependent protein kinase (PKA) and exchange proteins directly activated by cAMP (Epacs) (8-10). A recent study revealed that activation of Epacs by an Epac-selective cAMP analog, 8-CPT-2=-O-Me-cAMP (11), interferes with leptin signaling in the hypothalamus, suggesting that Epacs may contribute to the pathophysiology of leptin resistance and represent a novel pharmacological target for treatment of obesity (12). To investigate the functional significance of Epac1 in leptin-mediated energy balance in vivo, we generated global loss-of-function mutants for Epac1. Analysis of these animals indicated resistance to high-fat diet (HFD)-induced obesity, heightened leptin signaling in the arcuate nucleus (AN), and improved glucose tolerance. These findings reveal an important role of Epac1 in metabolism and suggest that Epac1 may represent a novel therapeutic target for obesity. MATERIALS AND METHODS Mice.To construct an Epac1 targeting vector, two loxP sites were inserted into introns 2 and 5. A 3.8-kb upstream ...

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EPAC Null Mutation Impairs Learning and Social Interactions via Aberrant Regulation of miR-124 and Zif268 Translation

Cited by 163 publications

References 58 publications

MicroRNAs: Small molecules with big roles in neurodevelopment and diseases

MicroRNAs: Small molecules with big roles in neurodevelopment and diseases

MicroRNAs and synaptic plasticity—a mutual relationship

Enhanced Leptin Sensitivity, Reduced Adiposity, and Improved Glucose Homeostasis in Mice Lacking Exchange Protein Directly Activated by Cyclic AMP Isoform 1

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