The PTEN/PI3K signaling pathway regulates a vast array of fundamental cellular responses. We show that cardiomyocyte-specific inactivation of tumor suppressor PTEN results in hypertrophy, and unexpectedly, a dramatic decrease in cardiac contractility. Analysis of double-mutant mice revealed that the cardiac hypertrophy and the contractility defects could be genetically uncoupled. PI3Kalpha mediates the alteration in cell size while PI3Kgamma acts as a negative regulator of cardiac contractility. Mechanistically, PI3Kgamma inhibits cAMP production and hypercontractility can be reverted by blocking cAMP function. These data show that PTEN has an important in vivo role in cardiomyocyte hypertrophy and GPCR signaling and identify a function for the PTEN-PI3Kgamma pathway in the modulation of heart muscle contractility.
microRNAs (miRNAs) are a class of small, noncoding RNAs that regulate the stability or translation of mRNA transcripts. Although recent work has implicated miRNAs in development and in disease, the expression and function of miRNAs in the adult mammalian nervous system have not been extensively characterized. Here, we examine the role of two brain-specific miRNAs, miR-219 and miR-132, in modulating the circadian clock located in the suprachiasmatic nucleus. miR-219 is a target of the CLOCK and BMAL1 complex, exhibits robust circadian rhythms of expression, and the in vivo knockdown of miR-219 lengthens the circadian period. miR-132 is induced by photic entrainment cues via a MAPK/CREB-dependent mechanism, modulates clock-gene expression, and attenuates the entraining effects of light. Collectively, these data reveal miRNAs as clock- and light-regulated genes and provide a mechanistic examination of their roles as effectors of pacemaker activity and entrainment.
Activity-regulated gene expression is believed to play a key role in the development and refinement of neuronal circuitry. Nevertheless, the transcriptional networks that regulate synapse growth and plasticity remain largely uncharacterized. Here, we show that microRNA 132 (miR132) is an activity-dependent rapid response gene regulated by the cAMP response element-binding (CREB) protein pathway. Introduction of miR132 into hippocampal neurons enhanced dendrite morphogenesis whereas inhibition of miR132 by 2 O-methyl RNA antagonists blocked these effects. Furthermore, neuronal activity inhibited translation of p250GAP, a miR132 target, and siRNA-mediated knockdown of p250GAP mimicked miR132-induced dendrite growth. Experiments using dominant-interfering mutants suggested that Rac signaling is downstream of miR132 and p250GAP. We propose that the miR132-p250GAP pathway plays a key role in activity-dependent structural and functional plasticity.cAMP response element-binding (CREB) protein ͉ transcription ͉ CaM kinase ͉ actin cytoskeleton ͉ Rac N euronal activity regulates the development and modification of neuronal circuitry in part by activating genetic programs. Activity-regulated gene expression has been implicated in axon guidance, dendrite elaboration, synapse formation, and long-lasting synaptic plasticity (1, 2). Dendrites are the primary site of excitatory synapses, and their morphogenesis determines both the size and number of synaptic contacts (3). Although dendritic development is partly controlled by intrinsic factors, neuronal activity also plays a critical role. Indeed, the timing of afferent innervation and synapse formation coincides with the period of maximum growth and dendritic remodeling (3).The transcription factor cAMP response element-binding (CREB) protein is a key regulator of dendritic growth (4) and activity-regulated dendritic refinement in mature neurons (5). Although CREB is believed to be a critical regulator of neuronal plasticity, few CREB targets have been directly linked to plasticity. To identify these genes, we developed a novel technology, termed serial analysis of chromatin occupancy (SACO) that facilitated the genome-wide identification of CREB target regions (6). We focused on microRNAs (miRNAs) because the ability of these molecules to repress gene expression is believed to play an important role in development, differentiation, proliferation, survival, and oncogenesis (7). Interestingly, a significant fraction of miRNAs are enriched or specifically expressed in the nervous system (8), and transcription of some miRNAs changes dynamically during brain development (9, 10). miRNAs have been implicated in development of neuronal asymmetry in Caenorhabditis elegans, maturation of sensory neurons in Drosophila, and neurite outgrowth and spine homeostasis in rodents (11)(12)(13)(14). Although activity is believed to play an essential role in sculpting neuronal development, miRNAs induced by neuronal activity have not been described.Here, we show that microRNA 132 (miR132) is an a...
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