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Joseph G. Culotti - One of the best experts on this subject based on the ideXlab platform.

  • The Wnt Frizzled Receptor MOM-5 Regulates the UNC-5 Netrin Receptor through Small GTPase-Dependent Signaling to Determine the Polarity of Migrating Cells
    PLOS Genetics, 2015
    Co-Authors: Naomi Levy-strumpf, Meghan Krizus, Hong Zheng, Louise Brown, Joseph G. Culotti
    Abstract:

    Wnt and Netrin signaling regulate diverse essential functions. Using a genetic approach combined with temporal gene expression analysis, we found a regulatory link between the Wnt Receptor MOM-5/Frizzled and the UNC-6/Netrin Receptor UNC-5. These two Receptors play key roles in guiding cell and axon migrations, including the migration of the C. elegans Distal Tip Cells (DTCs). DTCs migrate post-embryonically in three sequential phases: in the first phase along the Antero-Posterior (A/P) axis, in the second, along the Dorso-Ventral (D/V) axis, and in the third, along the A/P axis. Loss of MOM-5/Frizzled function causes third phase A/P polarity reversals of the migrating DTCs. We show that an over-expression of UNC-5 causes similar DTC A/P polarity reversals and that unc-5 deficits markedly suppress the A/P polarity reversals caused by mutations in mom-5/frizzled. This implicates MOM-5/Frizzled as a negative regulator of unc-5. We provide further evidence that small GTPases mediate MOM-5’s regulation of unc-5 such that one outcome of impaired function of small GTPases like CED-10/Rac and MIG-2/RhoG is an increase in unc-5 function. The work presented here demonstrates the existence of cross talk between components of the Netrin and Wnt signaling pathways and provides further insights into the way guidance signaling mechanisms are integrated to orchestrate directed cell migration.

  • regulation of the unc 5 Netrin Receptor initiates the first reorientation of migrating distal tip cells in caenorhabditis elegans
    Development, 2000
    Co-Authors: David C Merz, Hong Zheng, Marie T. Killeen, Edward M. Hedgecock, Youwen Zhou, James M Kramer, Joseph G. Culotti
    Abstract:

    Cell migrations play a critical role in animal development and organogenesis. Here, we describe a mechanism by which the migration behaviour of a particular cell type is regulated temporally and coordinated with over-all development of the organism. The hermaphrodite distal tip cells (DTCs) of Caenorhabditis elegans migrate along the body wall in three sequential phases distinguished by the orientation of their movements, which alternate between the anteroposterior and dorsoventral axes. The ventral-to-dorsal second migration phase requires the UNC-6 Netrin guidance cue and its Receptors UNC-5 and UNC-40, as well as additional, UNC-6-independent guidance systems. We provide evidence that the transcriptional upregulation of unc-5 in the DTCs is coincident with the initiation of the second migration phase, and that premature UNC-5 expression in these cells induces precocious turning in an UNC-6-dependent manner. The DAF-12 steroid hormone Receptor, which regulates developmental stage transitions in C. elegans, is required for initiating the first DTC turn and for coincident unc-5 upregulation. We also present evidence for the existence of a mechanism that opposes or inhibits UNC-5 function during the longitudinal first migration phase and for a mechanism that facilitates UNC-5 function during turning. The facilitating mechanism presumably does not involve transcriptional regulation of unc-5 but may represent an inhibition of the phase 1 mechanism that opposes or inhibits UNC-5. These results, therefore, reveal the existence of two mechanisms that regulate the UNC-5 Receptor that are critical for responsiveness to the UNC-6 Netrin guidance cue and for linking the directional guidance of migrating distal tip cells to developmental stage advancements.

  • Deleted in Colorectal Cancer (DCC) Encodes a Netrin Receptor
    Cell, 1996
    Co-Authors: Kazuko Keino-masu, Joseph G. Culotti, Masayuki Masu, Lindsay Hinck, E.david Leonardo, Shirley S.-y Chan, Marc Tessier-lavigne
    Abstract:

    The guidance of developing axons in the nervous system is mediated partly by diffusible chemoattractants secreted by axonal target cells. Netrins are chemoattractants for commissural axons in the vertebrate spinal cord, but the mechanisms through which they produce their effects are unknown. We show that Deleted in Colorectal Cancer (DCC), a transmembrane protein of the immunoglobulin superfamily, is expressed on spinal commissural axons and possesses Netrin-1-binding activity. Moreover, an antibody to DCC selectively blocks the Netrin-1-dependent outgrowth of commissural axons in vitro. These results indicate that DCC is a Receptor or a component of a Receptor that mediates the effects of Netrin-1 on commissural axons, and they complement genetic evidence for interactions between DCC and Netrin homologs in C. elegans and Drosophila.

  • UNC-40, a C. elegans Homolog of DCC (Deleted in Colorectal Cancer), Is Required in Motile Cells Responding to UNC-6 Netrin Cues
    Cell, 1996
    Co-Authors: S.s.-y. Chan, Hong Zheng, R. Wilk, Marie T. Killeen, Edward M. Hedgecock, Joseph G. Culotti
    Abstract:

    UNC-6 Netrin, a laminin-related protein secreted from neuroglia and neurons along the ventral midline, orients migrating cells and pioneering growth cones on the nematode epidermis. UNC-5, a cell surface protein expressed on motile cells and pioneer axons, orients movements away from UNC-6 sources. UNC-40, a homolog of the cell surface proteins DCC (Deleted in Colorectal Cancer) and neogenin, is also expressed on motile cells and pioneer neurons. UNC-40 acts cell autonomously to orient movement toward UNC-6 sources. For cells coexpressing UNC-5, it helps orient movement away from UNC-6 sources. Finally, UNC-40 helps determine the dorsoventral position of cells undergoing purely longitudinal migrations. Together with the recent report that DCC is a Netrin Receptor in vertebrates, our results suggest that UNC-40 is a component of UNC-6 Receptors on motile cells.

Yongsheng Zhou - One of the best experts on this subject based on the ideXlab platform.

Molly Dumanscheel - One of the best experts on this subject based on the ideXlab platform.

  • the drosophila Netrin Receptor frazzled dcc functions as an invasive tumor suppressor
    BMC Developmental Biology, 2011
    Co-Authors: Adrienne Vanzomerendohm, Joseph Sarro, Ellen Flannery, Molly Dumanscheel
    Abstract:

    Background Loss of heterozygosity at 18q, which includes the Deleted in Colorectal Cancer (DCC) gene, has been linked to many human cancers. However, it is unclear if loss of DCC is the specific underlying cause of these cancers. The Drosophila imaginal discs are excellent systems in which to study DCC function, as it is possible to model human tumors through the generation of somatic clones of cells bearing multiple genetic lesions. Here, these attributes of the fly system were utilized to investigate the potential tumor suppressing functions of the Drosophila DCC homologue frazzled (fra) during eye-antennal disc development.

  • the drosophila Netrin Receptor frazzled dcc functions as an invasive tumor suppressor
    BMC Developmental Biology, 2011
    Co-Authors: Adrienne Vanzomerendohm, Joseph Sarro, Ellen Flannery, Molly Dumanscheel
    Abstract:

    Loss of heterozygosity at 18q, which includes the Deleted in Colorectal Cancer (DCC) gene, has been linked to many human cancers. However, it is unclear if loss of DCC is the specific underlying cause of these cancers. The Drosophila imaginal discs are excellent systems in which to study DCC function, as it is possible to model human tumors through the generation of somatic clones of cells bearing multiple genetic lesions. Here, these attributes of the fly system were utilized to investigate the potential tumor suppressing functions of the Drosophila DCC homologue frazzled (fra) during eye-antennal disc development. Most fra loss of function clones are eliminated during development. However, when mutant clone cells generated in the developing eye were rescued from death, partially differentiated eye cells were found outside of the normal eye field, and in extreme cases distant sites of the body. Characterization of these cells during development indicates that fra mutant cells display characteristics of invasive tumor cells, including increased levels of phospho-ERK, phospho-JNK, and Mmp-1, changes in cadherin expression, remodeling of the actin cytoskeleton, and loss of polarity. Mutation of fra promotes basement membrane degradation and invasion which are repressed by inhibition of Rho1 signaling. Although inhibition of JNK signaling blocks invasive phenotypes in some metastatic cancer models in flies, blocking JNK signaling inhibits fra mutant cell death, thereby enhancing the fra mutant phenotype. The results of this investigation provide the first direct link between point mutations in fra/DCC and metastatic phenotypes in an animal model and suggest that Fra functions as an invasive tumor suppressor during Drosophila development.

Jean-louis Bessereau - One of the best experts on this subject based on the ideXlab platform.

  • the Netrin Receptor unc 40 dcc assembles a postsynaptic scaffold and sets the synaptic content of gabaa Receptors
    Nature Communications, 2020
    Co-Authors: Xin Zhou, Marine Gueydan, Maelle Jospin, Aurore Valfort, Berangere Pinanlucarre, Jean-louis Bessereau
    Abstract:

    Increasing evidence indicates that guidance molecules used during development for cellular and axonal navigation also play roles in synapse maturation and homeostasis. In C. elegans the Netrin Receptor UNC-40/DCC controls the growth of dendritic-like muscle cell extensions towards motoneurons and is required to recruit type A GABA Receptors (GABAARs) at inhibitory neuromuscular junctions. Here we show that activation of UNC-40 assembles an intracellular synaptic scaffold by physically interacting with FRM-3, a FERM protein orthologous to FARP1/2. FRM-3 then recruits LIN-2, the ortholog of CASK, that binds the synaptic adhesion molecule NLG-1/Neuroligin and physically connects GABAARs to prepositioned NLG-1 clusters. These processes are orchestrated by the synaptic organizer CePunctin/MADD-4, which controls the localization of GABAARs by positioning NLG-1/neuroligin at synapses and regulates the synaptic content of GABAARs through the UNC-40-dependent intracellular scaffold. Since DCC is detected at GABA synapses in mammals, DCC might also tune inhibitory neurotransmission in the mammalian brain.

  • c elegans punctin clusters gaba a Receptors via neuroligin binding and unc 40 dcc recruitment
    Neuron, 2015
    Co-Authors: Berangere Pinanlucarre, Maelle Jospin, Jean-louis Bessereau
    Abstract:

    Positioning type A GABA Receptors (GABA(A)Rs) in front of GABA release sites sets the strength of inhibitory synapses. The evolutionarily conserved Ce-Punctin/MADD-4 is an anterograde synaptic organizer that specifies GABAergic versus cholinergic identity of postsynaptic domains at the C. elegans neuromuscular junctions (NMJs). Here we show that the Ce-Punctin secreted by GABAergic motor neurons controls the clustering of GABA(A)Rs through the synaptic adhesion molecule neuroligin (NLG-1) and the Netrin Receptor UNC-40/DCC. The short isoform of Ce-Punctin binds and clusters NLG-1 postsynaptically at GABAergic NMJs. NLG-1 disruption causes a strong reduction of GABA(A)R content at GABAergic synapses. Ce-Punctin also binds and localizes UNC-40 Receptors in the postsynaptic membrane of NMJs, which promotes the recruitment of GABA(A)Rs by NLG-1. Since the mammalian orthologs of these genes are expressed in the central nervous system and their mutations are implicated in neuropsychiatric diseases, this molecular pathway might have been evolutionarily conserved.

Yunsong Liu - One of the best experts on this subject based on the ideXlab platform.