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Lee Tzumin Lab / Publications
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64 Publications

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    12/22/09 | Nuclear receptor unfulfilled regulates axonal guidance and cell identity of Drosophila mushroom body neurons.
    Lin S, Huang Y, Lee T
    PLoS One. 2009 Dec 22;4(12):e8392. doi: 10.1371/journal.pone.0008392

    Nuclear receptors (NRs) comprise a family of ligand-regulated transcription factors that control diverse critical biological processes including various aspects of brain development. Eighteen NR genes exist in the Drosophila genome. To explore their roles in brain development, we knocked down individual NRs through the development of the mushroom bodies (MBs) by targeted RNAi. Besides recapitulating the known MB phenotypes for three NRs, we found that unfulfilled (unf), an ortholog of human photoreceptor specific nuclear receptor (PNR), regulates axonal morphogenesis and neuronal subtype identity. The adult MBs develop through remodeling of gamma neurons plus de-novo elaboration of both alpha’/beta’ and alpha/beta neurons. Notably, unf is largely dispensable for the initial elaboration of gamma neurons, but plays an essential role in their re-extension of axons after pruning during early metamorphosis. The subsequently derived MB neuron types also require unf for extension of axons beyond the terminus of the pruned bundle. Tracing single axons revealed misrouting rather than simple truncation. Further, silencing unf in single-cell clones elicited misguidance of axons in otherwise unperturbed MBs. Such axon guidance defects may occur as MB neurons partially lose their subtype identity, as evidenced by suppression of various MB subtype markers in unf knockdown MBs. In sum, unf governs axonal morphogenesis of multiple MB neuron types, possibly through regulating neuronal subtype identity.

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    08/01/09 | New genetic tools for cell lineage analysis in Drosophila.
    Lee T
    Nature Methods. 2009 Aug;6(8):566-8. doi: 10.1038/nmeth0809-566

    Real-time lineage tracing in flies gets a boost with three techniques to specifically label a progenitor’s daughter cells.

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    07/01/09 | Twin-spot MARCM to reveal the developmental origin and identity of neurons.
    Yu H, Chen C, Shi L, Huang Y, Lee T
    Nature Neuroscience. 2009 Jul;12(7):947-53. doi: 10.1038/nn.2345

    A comprehensive understanding of the brain requires the analysis of individual neurons. We used twin-spot mosaic analysis with repressible cell markers (twin-spot MARCM) to trace cell lineages at high resolution by independently labeling paired sister clones. We determined patterns of neurogenesis and the influences of lineage on neuron-type specification. Notably, neural progenitors were able to yield intermediate precursors that create one, two or more neurons. Furthermore, neurons acquired stereotyped projections according to their temporal position in various brain sublineages. Twin-spot MARCM also permitted birth dating of mutant clones, enabling us to detect a single temporal fate that required chinmo in a sublineage of six Drosophila central complex neurons. In sum, twin-spot MARCM can reveal the developmental origins of neurons and the mechanisms that underlie cell fate.

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    02/11/09 | Endodomain diversity in the Drosophila Dscam and its roles in neuronal morphogenesis.
    Yu H, Yang JS, Wang J, Huang Y, Lee T
    The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2009 Feb 11;29(6):1904-14. doi: 10.1523/JNEUROSCI.5743-08.2009

    Drosophila Down syndrome cell adhesion molecule (Dscam) can be variably spliced to encode 152,064 distinct single-pass transmembrane proteins. In addition to 19,008 possible ectodomains and two alternative transmembrane segments, it may carry endodomains containing or lacking exons 19 and 23. Here, we determine the role of Dscam endodomain diversity in neural development. Dscam with full-length endodomain is largely restricted to embryogenesis. In contrast, most Dscams lack exons 19 and 23 at postembryonic stages. As implicated from the expression patterns, removal of Dscam exon 19-containing variants disrupts wiring of embryonic neurons while silencing of Dscam transcripts lacking exon 19 or exon 23 effectively blocks postembryonic neuronal morphogenesis. Furthermore, compared with exon 19-containing Dscam, transgenic Dscam without exon 19 is more efficiently targeted to neurites and more potently suppresses axon bifurcation in Dscam mutant neurons. In sum, Dscam with or without exon 19 in its endodomain is used to govern different stage-specific neuronal morphogenetic processes, possibly due to differences in protein targeting.

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    12/17/08 | Organization and postembryonic development of glial cells in the adult central brain of Drosophila.
    Awasaki T, Lai S, Ito K, Lee T
    The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2008 Dec 17;28(51):13742-53. doi: 10.1523/JNEUROSCI.4844-08.2008

    Glial cells exist throughout the nervous system, and play essential roles in various aspects of neural development and function. Distinct types of glia may govern diverse glial functions. To determine the roles of glia requires systematic characterization of glia diversity and development. In the adult Drosophila central brain, we identify five different types of glia based on its location, morphology, marker expression, and development. Perineurial and subperineurial glia reside in two separate single-cell layers on the brain surface, cortex glia form a glial mesh in the brain cortex where neuronal cell bodies reside, while ensheathing and astrocyte-like glia enwrap and infiltrate into neuropils, respectively. Clonal analysis reveals that distinct glial types derive from different precursors, and that most adult perineurial, ensheathing, and astrocyte-like glia are produced after embryogenesis. Notably, perineurial glial cells are made locally on the brain surface without the involvement of gcm (glial cell missing). In contrast, the widespread ensheathing and astrocyte-like glia derive from specific brain regions in a gcm-dependent manner. This study documents glia diversity in the adult fly brain and demonstrates involvement of different developmental programs in the derivation of distinct types of glia. It lays an essential foundation for studying glia development and function in the Drosophila brain.

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    09/01/08 | Clonal analysis of Drosophila antennal lobe neurons: diverse neuronal architectures in the lateral neuroblast lineage.
    Lai S, Awasaki T, Ito K, Lee T
    Development. 2008 Sep;135(17):2883-93. doi: 10.1242/dev.024380

    The antennal lobe (AL) is the primary structure in the Drosophila brain that relays odor information from the antennae to higher brain centers. The characterization of uniglomerular projection neurons (PNs) and some local interneurons has facilitated our understanding of olfaction; however, many other AL neurons remain unidentified. Because neuron types are mostly specified by lineage and temporal origins, we use the MARCM techniques with a set of enhancer-trap GAL4 lines to perform systematical lineage analysis to characterize neuron morphologies, lineage origin and birth timing in the three AL neuron lineages that contain GAL4-GH146-positive PNs: anterodorsal, lateral and ventral lineages. The results show that the anterodorsal lineage is composed of pure uniglomerular PNs that project through the inner antennocerebral tract. The ventral lineage produces uniglomerular and multiglomerular PNs that project through the middle antennocerebral tract. The lateral lineage generates multiple types of neurons, including uniglomeurlar PNs, diverse atypical PNs, various types of AL local interneurons and the neurons that make no connection within the ALs. Specific neuron types in all three lineages are produced in specific time windows, although multiple neuron types in the lateral lineage are made simultaneously. These systematic cell lineage analyses have not only filled gaps in the olfactory map, but have also exemplified additional strategies used in the brain to increase neuronal diversity.

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    06/20/07 | Specific Drosophila Dscam juxtamembrane variants control dendritic elaboration and axonal arborization.
    Shi L, Yu H, Yang JS, Lee T
    The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2007 Jun 20;27(25):6723-8. doi: 10.1523/JNEUROSCI.1517-07.2007

    Drosophila Dscam isoforms are derived from two alternative transmembrane/juxtamembrane domains (TMs) in addition to thousands of ectodomain variants. Using a microRNA-based RNA interference technology, we selectively knocked down different subsets of Dscams containing either the exon 17.1- or exon 17.2-encoding TM. Eliminating Dscam[TM1] reduced Dscam expression but minimally affected postembryonic axonal morphogenesis. In contrast, depleting Dscam[TM2] blocked axon arborization. Further removal of Dscam[TM1] enhanced the loss-of-Dscam[TM2] axonal phenotypes. However, Dscam[TM1] primarily regulates dendritic development, as evidenced by the observations that removing Dscam[TM1] alone impeded elaboration of dendrites and that transgenic Dscam[TM1], but not Dscam[TM2], effectively rescued Dscam mutant dendritic phenotypes in mosaic organisms. These distinct Dscam functions can be attributed to the juxtamembrane regions of TMs that govern dendritic versus axonal targeting of Dscam as well. Together, we suggest that specific Drosophila Dscam juxtamembrane variants control dendritic elaboration and axonal arborization.

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    10/20/06 | Gradients of the Drosophila Chinmo BTB-zinc finger protein govern neuronal temporal identity.
    Zhu S, Lin S, Kao C, Awasaki T, Chiang A, Lee T
    Cell. 2006 Oct 20;127(2):409-22. doi: 10.1016/j.cell.2006.08.045

    Many neural progenitors, including Drosophila mushroom body (MB) and projection neuron (PN) neuroblasts, sequentially give rise to different subtypes of neurons throughout development. We identified a novel BTB-zinc finger protein, named Chinmo (Chronologically inappropriate morphogenesis), that governs neuronal temporal identity during postembryonic development of the Drosophila brain. In both MB and PN lineages, loss of Chinmo autonomously causes early-born neurons to adopt the fates of late-born neurons from the same lineages. Interestingly, primarily due to a posttranscriptional control, MB neurons born at early developmental stages contain more abundant Chinmo than their later-born siblings. Further, the temporal identity of MB progeny can be transformed toward earlier or later fates by reducing or increasing Chinmo levels, respectively. Taken together, we suggest that a temporal gradient of Chinmo (Chinmo(high) –> Chinmo(low)) helps specify distinct birth order-dependent cell fates in an extended neuronal lineage.

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    05/01/06 | Genetic mosaic with dual binary transcriptional systems in Drosophila.
    Lai S, Lee T
    Nature Neuroscience. 2006 May;9(5):703-9. doi: 10.1038/nn1681

    MARCM (mosaic analysis with a repressible cell marker) involves specific labeling of GAL80-minus and GAL4-positive homozygous cells in otherwise heterozygous tissues. Here we demonstrate how the concurrent use of two independent binary transcriptional systems may facilitate complex MARCM studies in the Drosophila nervous system. By fusing LexA with the VP16 acidic activation domain (VP16) or the GAL4 activation domain (GAD), we obtained both GAL80-insensitive and GAL80-suppressible transcriptional factors. LexA::VP16 can mediate MARCM-independent binary transgene induction in mosaic organisms. The incorporation of LexA::GAD into MARCM, which we call dual-expression-control MARCM, permits the induction of distinct transgenes in different patterns among GAL80-minus cells in mosaic tissues. Lineage analysis with dual-expression-control MARCM suggested the presence of neuroglioblasts in the developing optic lobes but did not indicate the production of glia by postembryonic mushroom body neuronal precursors. In addition, dual-expression-control MARCM with a ubiquitous LexA::GAD driver revealed many unidentified cells in the GAL4-GH146-positive projection neuron lineages.

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    09/02/04 | Transmembrane/juxtamembrane domain-dependent Dscam distribution and function during mushroom body neuronal morphogenesis.
    Wang J, Ma X, Yang JS, Zheng X, Zugates CT, Lee CJ, Lee T
    Neuron. 2004 Sep 2;43(5):663-72. doi: 10.1016/j.neuron.2004.06.033

    Besides 19,008 possible ectodomains, Drosophila Dscam contains two alternative transmembrane/juxtamembrane segments, respectively, derived from exon 17.1 and exon 17.2. We wondered whether specific Dscam isoforms mediate formation and segregation of axonal branches in the Drosophila mushroom bodies (MBs). Removal of various subsets of the 12 exon 4s does not affect MB neuronal morphogenesis, while expression of a Dscam transgene only partially rescues Dscam mutant phenotypes. Interestingly, differential rescuing effects are observed between two Dscam transgenes that each possesses one of the two possible exon 17s. Axon bifurcation/segregation abnormalities are better rescued by the exon 17.2-containing transgene, but coexpression of both transgenes is required for rescuing mutant viability. Meanwhile, exon 17.1 targets ectopically expressed Dscam-GFP to dendrites while Dscam[exon 17.2]-GFP is enriched in axons; only Dscam[exon 17.2] affects MB axons. These results suggest that exon 17.1 is minimally involved in axonal morphogenesis and that morphogenesis of MB axons probably involves multiple distinct exon 17.2-containing Dscam isoforms.

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