MicroRNA Processing Pathway Regulates Olfactory Neuron Morphogenesis

Howard Hughes Medical Institute, Department of Biology, Stanford University, Stanford, CA 94305, USA.
Current Biology (Impact Factor: 9.57). 12/2008; 18(22):1754-9. DOI: 10.1016/j.cub.2008.09.045
Source: PubMed


The microRNA (miRNA) processing pathway produces miRNAs as posttranscriptional regulators of gene expression. The nuclear RNase III Drosha catalyzes the first processing step together with the dsRNA binding protein DGCR8/Pasha generating pre-miRNAs [1, 2]. The next cleavage employs the cytoplasmic RNase III Dicer producing miRNA duplexes [3, 4]. Finally, Argonautes are recruited with miRNAs into an RNA-induced silencing complex for mRNA recognition (Figure 1A). Here, we identify two members of the miRNA pathway, Pasha and Dicer-1, in a forward genetic screen for mutations that disrupt wiring specificity of Drosophila olfactory projection neurons (PNs). The olfactory system is built as discrete map of highly stereotyped neuronal connections [5, 6]. Each PN targets dendrites to a specific glomerulus in the antennal lobe and projects axons stereotypically into higher brain centers [7-9]. In selected PN classes, pasha and Dicer-1 mutants cause specific PN dendrite mistargeting in the antennal lobe and altered axonal terminations in higher brain centers. Furthermore, Pasha and Dicer-1 act cell autonomously in postmitotic neurons to regulate dendrite and axon targeting during development. However, Argonaute-1 and Argonaute-2 are dispensable for PN morphogenesis. Our findings suggest a role for the miRNA processing pathway in establishing wiring specificity in the nervous system.

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    • "Thus, Capricious and Tartan instruct the targeting of PN dendrites to discrete glomeruli. Forward genetic screens and candidate approaches have uncovered many other molecules that are cellautonomously required for the targeting of PN dendrites to specific glomeruli—Rpd3 (major histone deacetylase), Bap55 (chromatin remodeling factor), Pasha and Dicer-1 (members of the microRNA processing pathway), Verloren (small ubiquitin-like modifier protease), cohesin SA and SMC1 (multisubunit complex required for sister-chromatid cohesion during mitosis and meiosis), and Unc-51 (regulator of vesicle trafficking along microtubule)—are all reported to regulate proper dendrite targeting of PNs (Tea et al., 2010; Tea and Luo, 2011; Berdnik et al., 2008, 2012; Schuldiner et al., 2008; Mochizuki et al., 2011). In addition to these intrinsic machineries, interactions between PNs and other cell types also contribute to proper PN dendrite targeting and the synaptic matching between dendrites of specific type of PNs and axons of corresponding ORNs. "
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    ABSTRACT: The antennal lobe (AL) of Drosophila is the first olfactory processing center in which olfactory input and output are spatially organized into distinct channels via glomeruli to form a discrete neural map. In each glomerulus, the axons of a single type of olfactory receptor neurons (ORNs) synapse with the dendrites of a single type of projection neurons (PNs). The AL is an ideal place to study how the wiring specificity between specific types of ORNs and PNs is established during development. During the past two decades, the involvement of diverse molecules in the specification and patterning of ORNs and PNs has been reported. Furthermore, local interneurons-another component of glomeruli-have been recently catalogued and their functions have been gradually dissected. Although there is accumulating knowledge about the involvement of these three cell types in the wiring specificity of the olfactory system, in this review, we focus especially on the development of PN dendrites.
    Preview · Article · May 2014 · Genes & Genetic Systems
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    • "A number of transcription factors have been identified to link lineage and birth timing with dendrite targeting specificity of the 50 PN classes (Komiyama et al. 2003; Zhu et al. 2006b; Komiyama and Luo 2007; Spletter et al. 2007). Furthermore, genetic screens for genes regulating PN dendrite targeting isolated mutants involved in multiple biological regulatory processes, including chromatin remodeling (Tea et al. 2010; Tea and Luo 2011), microRNA processing (Berdnik et al. 2008), protein translation (Chihara et al. 2007), glycosylation (Sekine et al. 2013), and sumoylation (Berdnik et al. 2012). Thus, it is clear that a variety of processes contribute to the specification of PN target choice, presumably by regulating the expression of cell-surface molecules, the key effectors for cell– cell interactions. "
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    ABSTRACT: Precise connections established between pre- and postsynaptic partners during development are essential for the proper function of the nervous system. The olfactory system detects a wide variety of odorants and processes the information in a precisely connected neural circuit. A common feature of the olfactory systems from insects to mammals is that the olfactory receptor neurons (ORNs) expressing the same odorant receptor make one-to-one connections with a single class of second-order olfactory projection neurons (PNs). This represents one of the most striking examples of targeting specificity in developmental neurobiology. Recent studies have uncovered central roles of transmembrane and secreted proteins in organizing this one-to-one connection specificity in the olfactory system. Here, we review recent advances in the understanding of how this wiring specificity is genetically controlled and focus on the mechanisms by which transmembrane and secreted proteins regulate different stages of the Drosophila olfactory circuit assembly in a coordinated manner. We also discuss how combinatorial coding, redundancy, and error-correcting ability could contribute to constructing a complex neural circuit in general.
    Full-text · Article · Jan 2014 · Genetics
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    • "This approach identified numerous functions of miRNAs in the nervous system such as their regulatory role in neurogenesis, synaptogenesis, differentiation, and plasticity [21], [24], [33], [34]. These small RNAs were also shown to regulate many sensory systems such as the visual [35]–[37] and olfactory systems [38], [39], taste [40], [41], CO2 sensing [42], and pain perception [43]. Studies in the auditory system revealed an essential role of miRNAs in the cochlea. "
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    ABSTRACT: Histogenesis of the auditory system requires extensive molecular orchestration. Recently, Dicer1, an essential gene for generation of microRNAs, and miR-96 were shown to be important for development of the peripheral auditory system. Here, we investigated their role for the formation of the auditory brainstem. Egr2::Cre-mediated early embryonic ablation of Dicer1 caused severe disruption of auditory brainstem structures. In adult animals, the volume of the cochlear nucleus complex (CNC) was reduced by 73.5%. This decrease is in part attributed to the lack of the microneuronal shell. In contrast, fusiform cells, which similar to the granular cells of the microneural shell are derived from Egr2 positive cells, were still present. The volume reduction of the CNC was already present at birth (67.2% decrease). The superior olivary complex was also drastically affected in these mice. Nissl staining as well as Vglut1 and Calbindin 1 immunolabeling revealed that principal SOC nuclei such as the medial nucleus of the trapezoid body and the lateral superior olive were absent. Only choline acetyltransferase positive neurons of the olivocochlear bundle were observed as a densely packed cell group in the ventrolateral area of the SOC. Mid-embryonic ablation of Dicer1 in the ventral cochlear nucleus by Atoh7::Cre-mediated recombination resulted in normal formation of the cochlear nucleus complex, indicating an early embryonic requirement of Dicer1. Quantitative RT-PCR analysis of miR-96 demonstrated low expression in the embryonic brainstem and up-regulation thereafter, suggesting that other microRNAs are required for proper histogenesis of the auditory brainstem. Together our data identify a critical role of Dicer activity during embryonic development of the auditory brainstem.
    Full-text · Article · Nov 2012 · PLoS ONE
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