Regulated microRNA biogenesis generates specificity in pro-growth neuronal gene expression
Ruiz, Claudia Roxana
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Control of translation is a fundamental source of regulating gene expression. Brain-derived neurotrophic factor (BDNF) is a critical activity-dependent modulator of gene expression, which can regulate both transcription and translation. Several functions of BDNF, including the induction of dendrite outgrowth and long-term synaptic plasticity, depend upon the ability of BDNF to regulate protein synthesis. Although BDNF modestly increases total neuronal protein synthesis, substantial evidence indicates that BDNF induces translation of only a small subset of expressed mRNAs and demonstrates an extraordinary degree of transcript specificity. The mechanism by which BDNF selectively upregulates the translation of only a discrete group of mRNAs is of intrinsic importance to its trophic function in promoting neuronal growth and plasticity, but how BDNF selects only a minority of expressed mRNAs is poorly understood. My thesis work addressed this question and led to the finding that BDNF rapidly elevates Dicer, increasing mature microRNA (miRNA) levels and inducing mRNA repression. BDNF also rapidly induces Lin28, an RNA binding protein, causing selective loss of Lin28-regulated miRNAs and a corresponding upregulation in translation of their target mRNAs. Loss of Lin28, or expression of a Lin28-resistant Let-7 precursor miRNA, inhibits BDNF translation specificity and BDNF-dependent dendrite arborization. The finding that Lin28 could be upregulated in mature neurons and was required for the specificity of BDNF-induced protein synthesis, led to the second portion of my thesis research, which investigates the molecular mechanism responsible for rapid transcription-independent induction of Lin28 by BDNF. This portion of my doctoral work demonstrated that TAR-RNA-binding protein (TRBP), a critical miRNA biogenesis component and Dicer binding partner, is required for the induction of Lin28 by BDNF and revealed that TRBP is a novel Lin28 binding partner. My dissertation sheds light on novel mechanisms of specificity in stimulus-dependent gene expression and offers a mechanistic understanding of how neuronal protein composition is controlled through induction of Lin28 in mature neurons. In addition, my thesis work elucidated cellular pathways underlying plasticity and established molecular links between neuronal pro-growth pathways and pluripotency, which may help us understand the dysregulated translation associated with cognitive disorders and diseases of the central nervous system.