The serotonin transporter (SERT) ensures the recapture of serotonin and is the pharmacological target of selective serotonin reuptake inhibitor (SSRI) antidepressants. We show that SERT is a target of microRNA-16 (miR-16). miR-16 is expressed at higher levels in noradrenergic than in serotonergic cells; its reduction in noradrenergic neurons causes de novo SERT expression. In mice, chronic treatment with the SSRI fluoxetine (Prozac) increases miR-16 levels in serotonergic raphe nuclei, which reduces SERT expression. Further, raphe exposed to fluoxetine release the neurotrophic factor S100β, which acts on noradrenergic cells of the locus coeruleus. By decreasing miR-16, S100β turns on the expression of serotonergic functions in noradrenergic neurons. Based on pharmacological and behavioral data, we propose that miR-16 contributes to the therapeutic action of SSRI antidepressants in monoaminergic neurons.

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Akt/protein kinase B (PKB) plays a critical role in the regulation of metabolism, transcription, cell migration, cell cycle progression, and cell survival. The existence of viable knockout mice for each of the three isoforms suggests functional redundancy. We generated mice with combined mutant alleles of Akt1 and Akt3 to study their effects on mouse development. Here we show that Akt1 ؊/؊ Akt3 ؉/؊ mice display multiple defects in the thymus, heart, and skin and die within several days after birth, while Akt1 ؉/؊ Akt3 ؊/؊ mice survive normally. Double knockout (Akt1 ؊/؊ Akt3 ؊/؊ ) causes embryonic lethality at around embryonic days 11 and 12, with more severe developmental defects in the cardiovascular and nervous systems. Increased apoptosis was found in the developing brain of double mutant embryos. These data indicate that the Akt1 gene is more essential than Akt3 for embryonic development and survival but that both are required for embryo development. Our results indicate isoform-specific and dosage-dependent effects of Akt on animal survival and development.In mammals, Akt1, Akt2, and Akt3 (also called protein kinase B␣ [PKB␣], PKB␤, and PKB␥) proteins have similar domain structures and can be activated by numerous growth factors in a phosphatidylinositol 3-kinase-dependent manner (1,3,4,15,23). Once activated, Akt phosphorylates and controls the activities of a diverse group of substrates involved in many cellular and physiological processes, such as cell survival, cell cycle progression, cell growth, metabolism, and angiogenesis (3,10,17,23).Although many proteins have been identified as Akt substrates, the challenge that remains is to show that they actually have an important impact on physiological processes in organisms. Recently, targeted deletion of specific isoforms of Akt in mice has proved to be a powerful tool for elucidating the physiological roles of Akt proteins (5,7,8,13,16,25,27,28). Characterization of such knockout mice has yielded intriguing and surprising results. We and others found that ϳ40% of Akt1 knockout mice die at a neonatal stage with growth retardation, but the other ϳ60% of Akt1 knockout mice survive apparently normally. This suggests that the other two remaining Akt isoforms can, in part, compensate for the loss of one Akt. Knockout of each single isoform gives rise to a distinct phenotype. In general, Akt1 null mice are growth retarded, which may result from placental insufficiency, while Akt2-deficient mice suffer from a type 2 diabetes-like syndrome and Akt3 null mice show impaired brain development (5,7,8,13,16,25,27,28). These observations indicate that the three Akt isoforms have different nonredundant physiological functions. The relatively normal development and distinct physiological functions exhibited by single knockouts may be explained by differences in the tissue distribution and expression levels of these isoforms. We found that Akt1 is the major isoform in placenta and that placenta lacking this protein cannot form a proper vascular labyrinth; this may restric...

The genetic manipulation of mice has become an essential and elegant method for studying the function of proteins in physiology, and for testing the veracity of information obtained from cell culture experiments. During the past few years, a variety of transgenic and knockout mouse models of PKB (protein kinase B)/Akt have been generated and investigated. In this paper, we focus on the phenotypes of these PKB/Akt overexpression and mutant mice that may help to elucidate the functions exerted by PKB/Akt in mammals.