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50 Janelia Publications

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    08/15/13 | Diverse neuronal lineages make stereotyped contributions to the Drosophila locomotor control center, the central complex.
    Yang JS, Awasaki T, Yu H, He Y, Ding P, Kao J, Lee T
    The Journal of Comparative Neurology. 2013 Aug 15;521(12):2645-62, Spc1. doi: 10.1002/cne.23339

    The Drosophila central brain develops from a fixed number of neuroblasts. Each neuroblast makes a clone of neurons that exhibit common trajectories. Here we identified 15 distinct clones that carry larval-born neurons innervating the Drosophila central complex (CX), which consists of four midline structures including the protocerebral bridge (PB), fan-shaped body (FB), ellipsoid body (EB), and noduli (NO). Clonal analysis revealed that the small-field CX neurons, which establish intricate projections across different CX substructures, exist in four isomorphic groups that respectively derive from four complex posterior asense-negative lineages. In terms of the region-characteristic large-field CX neurons, we found that two lineages make PB neurons, 10 lineages produce FB neurons, three lineages generate EB neurons, and two lineages yield NO neurons. The diverse FB developmental origins reflect the discrete input pathways for different FB subcompartments. Clonal analysis enlightens both development and anatomy of the insect locomotor control center.

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    04/22/13 | Clonal development and organization of the adult Drosophila central brain.
    Yu H, Awasaki T, Schroeder MD, Long F, Yang JS, He Y, Ding P, Kao J, Wu GY, Peng H, Myers G, Lee T
    Current biology : CB. 2013 Apr 22;23:633-43. doi: 10.1016/j.cub.2013.02.057

    BACKGROUND: The insect brain can be divided into neuropils that are formed by neurites of both local and remote origin. The complexity of the interconnections obscures how these neuropils are established and interconnected through development. The Drosophila central brain develops from a fixed number of neuroblasts (NBs) that deposit neurons in regional clusters. RESULTS: By determining individual NB clones and pursuing their projections into specific neuropils, we unravel the regional development of the brain neural network. Exhaustive clonal analysis revealed 95 stereotyped neuronal lineages with characteristic cell-body locations and neurite trajectories. Most clones show complex projection patterns, but despite the complexity, neighboring clones often coinnervate the same local neuropil or neuropils and further target a restricted set of distant neuropils. CONCLUSIONS: These observations argue for regional clonal development of both neuropils and neuropil connectivity throughout the Drosophila central brain.

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    11/20/12 | Lineage analysis of Drosophila lateral antennal lobe neurons reveals notch-dependent binary temporal fate decisions.
    Lin S, Kao C, Yu H, Huang Y, Lee T
    PLoS Biology. 2012 Nov 20;10(11):e1001425. doi: 10.1371/journal.pbio.1001425

    Binary cell fate decisions allow the production of distinct sister neurons from an intermediate precursor. Neurons are further diversified based on the birth order of intermediate precursors. Here we examined the interplay between binary cell fate and birth-order-dependent temporal fate in the Drosophila lateral antennal lobe (lAL) neuronal lineage. Single-cell mapping of the lAL lineage by twin-spot mosaic analysis with repressible cell markers (ts-MARCM) revealed that projection neurons (PNs) and local interneurons (LNs) are made in pairs through binary fate decisions. Forty-five types of PNs innervating distinct brain regions arise in a stereotyped sequence; however, the PNs with similar morphologies are not necessarily born in a contiguous window. The LNs are morphologically less diverse than the PNs, and the sequential morphogenetic changes in the two pairs occur independently. Sanpodo-dependent Notch activity promotes and patterns the LN fates. By contrast, Notch diversifies PN temporal fates in a Sanpodo-dispensable manner. These pleiotropic Notch actions underlie the differential temporal fate specification of twin neurons produced by common precursors within a lineage, possibly by modulating postmitotic neurons’ responses to Notch-independent transcriptional cascades.

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    10/08/12 | The bHLH repressor Deadpan regulates the self-renewal and specification of Drosophila larval neural stem cells independently of Notch.
    Zhu S, Wildonger J, Barshow S, Younger S, Huang Y, Lee T
    PLoS One. 2012 Oct 8;7(10):e46724. doi: 10.1371/journal.pone.0046724

    Neural stem cells (NSCs) are able to self-renew while giving rise to neurons and glia that comprise a functional nervous system. However, how NSC self-renewal is maintained is not well understood. Using the Drosophila larval NSCs called neuroblasts (NBs) as a model, we demonstrate that the Hairy and Enhancer-of-Split (Hes) family protein Deadpan (Dpn) plays important roles in NB self-renewal and specification. The loss of Dpn leads to the premature loss of NBs and truncated NB lineages, a process likely mediated by the homeobox protein Prospero (Pros). Conversely, ectopic/over-expression of Dpn promotes ectopic self-renewing divisions and maintains NB self-renewal into adulthood. In type II NBs, which generate transit amplifying intermediate neural progenitors (INPs) like mammalian NSCs, the loss of Dpn results in ectopic expression of type I NB markers Asense (Ase) and Pros before these type II NBs are lost at early larval stages. Our results also show that knockdown of Notch leads to ectopic Ase expression in type II NBs and the premature loss of type II NBs. Significantly, dpn expression is unchanged in these transformed NBs. Furthermore, the loss of Dpn does not inhibit the over-proliferation of type II NBs and immature INPs caused by over-expression of activated Notch. Our data suggest that Dpn plays important roles in maintaining NB self-renewal and specification of type II NBs in larval brains and that Dpn and Notch function independently in regulating type II NB proliferation and specification.

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    02/23/12 | Hierarchical deployment of factors regulating temporal fate in a diverse neuronal lineage of the Drosophila central brain.
    Kao C, Yu H, He Y, Kao J, Lee T
    Neuron. 2012 Feb 23;73(4):677-84. doi: 10.1016/j.neuron.2011.12.018

    The anterodorsal projection neuron lineage of Drosophila melanogaster produces 40 neuronal types in a stereotypic order. Here we take advantage of this complete lineage sequence to examine the role of known temporal fating factors, including Chinmo and the Hb/Kr/Pdm/Cas transcriptional cascade, within this diverse central brain lineage. Kr mutation affects the temporal fate of the neuroblast (NB) itself, causing a single fate to be skipped, whereas Chinmo null only elicits fate transformation of NB progeny without altering cell counts. Notably, Chinmo operates in two separate windows to prevent fate transformation (into the subsequent Chinmo-indenpendent fate) within each window. By contrast, Hb/Pdm/Cas play no detectable role, indicating that Kr either acts outside of the cascade identified in the ventral nerve cord or that redundancy exists at the level of fating factors. Therefore, hierarchical fating mechanisms operate within the lineage to generate neuronal diversity in an unprecedented fashion.

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    01/01/12 | Generating neuronal diversity in the Drosophila central nervous system.
    Lin S, Lee T
    Developmental Dynamics: An Official Publication of the American Association of Anatomists. 2012 Jan;241:57-68. doi: 10.1002/dvdy.22739

    Generating diverse neurons in the central nervous system involves three major steps. First, heterogeneous neural progenitors are specified by positional cues at early embryonic stages. Second, neural progenitors sequentially produce neurons or intermediate precursors that acquire different temporal identities based on their birth-order. Third, sister neurons produced during asymmetrical terminal mitoses are given distinct fates. Determining the molecular mechanisms underlying each of these three steps of cellular diversification will unravel brain development and evolution. Drosophila has a relatively simple and tractable CNS, and previous studies on Drosophila CNS development have greatly advanced our understanding of neuron fate specification. Here we review those studies and discuss how the lessons we have learned from fly teach us the process of neuronal diversification in general.

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    01/01/12 | Molecular diversity of Dscam and self-recognition.
    Shi L, Lee T
    Advances in Experimental Medicine and Biology. 2012;739:262-75. doi: 10.1007/978-1-4614-1704-0_17

    Cell recognition requires interactions through molecules located on cell surface. The insect homolog of Down syndrome cell adhesion molecule (Dscam) manifests huge molecular diversity in its extracellular domain. High-affinity Dscam-Dscam interactions only occur between isoforms that carry identical extracellular domains. Homophilic Dscam signaling can, thus, vary in strength depending on the compositions of Dscams present on the opposing cell surfaces. Dscam abundantly exists in the developing nervous system and governs arborization and proper elaboration of neurites. Notably, individual neurons may stochastically and dynamically express a small subset of Dscam isoforms such that any given neurite can be endowed with a unique repertoire of Dscams. This allows individual neurites to recognize their sister branches. Self-recognition leads to self-repulsion, ensuring divergent migration of sister processes. By contrast, weak homophilic Dscam interactions may promote fasciculation of neurites that express analogous, but not identical, Dscams. Differential Dscam binding may provide graded cell recognition that in turn governs complex neuronal morphogenesis.

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    01/01/12 | Use of a Drosophila genome-wide conserved sequence database to identify functionally related cis-regulatory enhancers.
    Brody T, Yavatkar AS, Kuzin A, Kundu M, Tyson LJ, Ross J, Lin T, Lee C, Awasaki T, Lee T, Odenwald WF
    Developmental Dynamics: An Official Publication of the American Association of Anatomists. 2012 Jan;241:169-89. doi: 10.1002/dvdy.22728

    Phylogenetic footprinting has revealed that cis-regulatory enhancers consist of conserved DNA sequence clusters (CSCs). Currently, there is no systematic approach for enhancer discovery and analysis that takes full-advantage of the sequence information within enhancer CSCs.

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    10/01/11 | Anisotropic path searching for automatic neuron reconstruction.
    Xie J, Zhao T, Lee T, Myers E, Peng H
    Medical Image Analysis. 2011 Oct;15:680-9. doi: 10.1016/j.media.2011.05.013

    Full reconstruction of neuron morphology is of fundamental interest for the analysis and understanding of their functioning. We have developed a novel method capable of automatically tracing neurons in three-dimensional microscopy data. In contrast to template-based methods, the proposed approach makes no assumptions about the shape or appearance of neurite structure. Instead, an efficient seeding approach is applied to capture complex neuronal structures and the tracing problem is solved by computing the optimal reconstruction with a weighted graph. The optimality is determined by the cost function designed for the path between each pair of seeds and by topological constraints defining the component interrelations and completeness. In addition, an automated neuron comparison method is introduced for performance evaluation and structure analysis. The proposed algorithm is computationally efficient and has been validated using different types of microscopy data sets including Drosophila’s projection neurons and fly neurons with presynaptic sites. In all cases, the approach yielded promising results.

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    09/01/11 | New tools for the analysis of glial cell biology in Drosophila.
    Awasaki T, Lee T
    Glia. 2011 Sep;59(9):1377-86. doi: 10.1002/glia.21133

    Because of its genetic, molecular, and behavioral tractability, Drosophila has emerged as a powerful model system for studying molecular and cellular mechanisms underlying the development and function of nervous systems. The Drosophila nervous system has fewer neurons and exhibits a lower glia:neuron ratio than is seen in vertebrate nervous systems. Despite the simplicity of the Drosophila nervous system, glial organization in flies is as sophisticated as it is in vertebrates. Furthermore, fly glial cells play vital roles in neural development and behavior. In addition, powerful genetic tools are continuously being created to explore cell function in vivo. In taking advantage of these features, the fly nervous system serves as an excellent model system to study general aspects of glial cell development and function in vivo. In this article, we review and discuss advanced genetic tools that are potentially useful for understanding glial cell biology in Drosophila.

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