Juan-Pablo Labrador

Publications (13) View all

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  Available from: Juan-Pablo Labrador

  Article: A GATA/homeodomain transcriptional code regulates axon guidance through the Unc-5 receptor.

  Aref Arzan Zarin, Amanda C Daly, Jörn Hülsmeier, Jamshid Asadzadeh, Juan-Pablo Labrador
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  ABSTRACT: Transcription factor codes play an essential role in neuronal specification and axonal guidance in both vertebrate and invertebrate organisms. However, how transcription codes regulate axon pathfinding remains poorly understood. One such code defined by the homeodomain transcription factor Even-skipped (Eve) and by the GATA 2/3 homologue Grain (Grn) is specifically required for motor axon projection towards dorsal muscles in Drosophila. Using different mutant combinations, we present genetic evidence that both Grn and Eve are in the same pathway as Unc-5 in dorsal motoneurons (dMNs). In grn mutants, in which dMNs fail to reach their muscle targets, dMNs show significantly reduced levels of unc-5 mRNA expression and this phenotype can be partially rescued by the reintroduction of unc-5. We also show that both eve and grn are required independently to induce expression of unc-5 in dMNs. Reconstitution of the eve-grn transcriptional code of a dMN in dMP2 neurons, which do not project to lateral muscles in Drosophila, is able to reprogramme those cells accordingly; they robustly express unc-5 and project towards the muscle field as dMNs. Each transcription factor can independently induce unc-5 expression but unc-5 expression is more robust when both factors are expressed together. Furthermore, dMP2 exit is dependent on the level of unc-5 induced by eve and grn. Taken together, our data strongly suggests that the eve-grn transcriptional code controls axon guidance, in part, by regulating the level of unc-5 expression.
  Development 03/2012; 139(10):1798-805. · 6.60 Impact Factor
• Article: Protein coadaptation and the design of novel approaches to identify protein-protein interactions.

  Mario A Fares, Mario X Ruiz-González, Juan Pablo Labrador
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  ABSTRACT: Proteins rarely function in isolation but they form part of complex networks of interactions with other proteins within or among cells. The importance of a particular protein for cell viability is directly dependent upon the number of interactions where it participates and the function it performs: the larger the number of interactions of a protein the greater its functional importance is for the cell. With the advent of genome sequencing and "omics" technologies it became feasible conducting large-scale searches for protein interacting partners. Unfortunately, the accuracy of such analyses has been underwhelming owing to methodological limitations and to the inherent complexity of protein interactions. In addition to these experimental approaches, many computational methods have been developed to identify protein-protein interactions by assuming that interacting proteins coevolve resulting from the coadaptation dynamics between the amino acids of their interacting faces. We review the main technological advances made in the field of interactomics and discuss the feasibility of computational methods to identify protein-protein interactions based on the estimation of coevolution. As proof-of-concept, we present a classical case study: the interactions of cell surface proteins (receptors) and their ligands. Finally, we take this discussion one step forward to include interactions between organisms and species to understand the generation of biological complexity. Development of technologies for accurate detection of protein-protein interactions may shed light on processes that go from the fine-tuning of pathways and metabolic networks to the emergence of biological complexity.
  International Union of Biochemistry and Molecular Biology Life 04/2011; 63(4):264-71. · 3.51 Impact Factor
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  Available from: Juan-Pablo Labrador

  Article: The Adam family metalloprotease Kuzbanian regulates the cleavage of the roundabout receptor to control axon repulsion at the midline.

  Hope A Coleman, Juan-Pablo Labrador, Rebecca K Chance, Greg J Bashaw
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  ABSTRACT: Slits and their Roundabout (Robo) receptors mediate repulsive axon guidance at the Drosophila ventral midline and in the vertebrate spinal cord. Slit is cleaved to produce fragments with distinct signaling properties. In a screen for genes involved in Slit-Robo repulsion, we have identified the Adam family metalloprotease Kuzbanian (Kuz). Kuz does not regulate midline repulsion through cleavage of Slit, nor is Slit cleavage essential for repulsion. Instead, Kuz acts in neurons to regulate repulsion and Kuz can cleave the Robo extracellular domain in Drosophila cells. Genetic rescue experiments using an uncleavable form of Robo show that this receptor does not maintain normal repellent activity. Finally, Kuz activity is required for Robo to recruit its downstream signaling partner, Son of sevenless (Sos). These observations support the model that Kuz-directed cleavage is important for Robo receptor activation.
  Development 07/2010; 137(14):2417-26. · 6.60 Impact Factor
• Article: The homeobox transcription factor even-skipped regulates netrin-receptor expression to control dorsal motor-axon projections in Drosophila.

  Juan Pablo Labrador, David O'keefe, Shingo Yoshikawa, Randall D McKinnon, John B Thomas, Greg J Bashaw
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  ABSTRACT: Homeobox transcription-factor codes control motor-neuron subtype identity and dorsal versus ventral axon guidance in both vertebrate and invertebrate nervous systems; however, the specific axon guidance-receptors that are regulated by these transcription factors to control pathfinding are poorly defined. In Drosophila, the Even-skipped (Eve) transcription factor specifies dorsal motor-axon projection through the regulation of unidentified guidance molecules. The Netrins and their attractive and repulsive receptors DCC and Unc-5, respectively, define important conserved cue and receptor families that control growth-cone guidance. In Drosophila, the Netrins and frazzled (the fly homolog of DCC) contribute to motor-axon guidance. Here, using genetics and single-cell mRNA-expression analysis, we show that expression and requirement of different Netrin receptor combinations correlate with distinct dorsal and ventral motor-axon projections in Drosophila. Mis-expression of eve dorsalizes ventral axons in part through the upregulation of Unc-5, whereas loss of eve function in two dorsally projecting motor neurons results in aberrant axon projections and a failure to express Unc-5. Our results support a functional link between the expression of distinct Netrin receptor combinations and the transcriptional control of dorsal motor-axon guidance.
  Current Biology 09/2005; 15(15):1413-9. · 9.65 Impact Factor
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  Available from: Juan-Pablo Labrador

  Article: Cross GTPase-activating protein (CrossGAP)/Vilse links the Roundabout receptor to Rac to regulate midline repulsion.

  Hailan Hu, Ming Li, Juan-Pablo Labrador, Jason McEwen, Eric C Lai, Corey S Goodman, Greg J Bashaw
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  ABSTRACT: The regulators of the Rho-family GTPases, GTPase-activating proteins (GAPs) and guanine exchange factors (GEFs), play important roles in axon guidance. By means of a functional genomic study of the Rho-family GEFs and GAPs in Drosophila, we have identified a Rho-family GAP, CrossGAP (CrGAP), which is involved in Roundabout (Robo) receptor-mediated repulsive axon guidance. CrGAP physically associates with the Robo receptor. Too much or too little CrGAP activity leads to defects in Robo-mediated repulsion at the midline choice point. The CrGAP gain-of-function phenotype mimics the loss-of-function phenotypes of both Robo and Rac. Dosage-sensitive genetic interactions among CrGAP, Robo, and Rac support a model in which CrGAP transduces signals downstream of Robo receptor to regulate Rac-dependent cytoskeletal changes.
  Proceedings of the National Academy of Sciences 04/2005; 102(12):4613-8. · 9.68 Impact Factor