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Williams Syndrome

Williams Syndrome. Natalie DeCheck. Image from: http://mindbodyshift.wordpress.com/2010/05/18/an-unquenchable-thirst-for-love-the-paradox-of-living-with-williams-syndrome/. What is Williams Syndrome?. Physical characteristics: “elfin” facial features narrowing of aorta or pulmonary arteries

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Williams Syndrome

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  1. Williams Syndrome • Natalie DeCheck Image from: http://mindbodyshift.wordpress.com/2010/05/18/an-unquenchable-thirst-for-love-the-paradox-of-living-with-williams-syndrome/

  2. What is Williams Syndrome? • Physical characteristics: • “elfin” facial features • narrowing of aorta or pulmonary arteries • musculoskeletal problems • sensitive hearing • short stature and slow weight gain • Behavioral characteristics: • exceptional music and linguistic abilities • poor numerical abilities • lack of visuospatial abilities • lack of social inhibition • mental retardation • general anxiety

  3. What is Williams Syndrome? Image from : Bellugi, U.,Wang, P. P., & Jernigan, T. L. (1994).Williams syndrome: An unusual neuropsychological profile. In S. H. Broman & J. Grafman (Eds.), A typical cognitive deficits in developmentaldisorders: Implications for brain function (pp. 23–56). Hillsdale, NJ: Lawrence Erlbaum.

  4. What causes Williams Syndrome? Image from: Francke U. Williams-Beuren syndrome: genes and mechanisms. Hum Mol Genet. 1999;8:1947–1954.

  5. LIMK1 affects visuospatial cognition http://neuralmodel.net/library/brain/parietal_cortex.htm

  6. ... But how? Biological Processes Rho protein signal transduction, actin cytoskeleton organization, axon guidance, negative regulation of ubiquitin protein ligase activity, positive regulation of actin filament bundle assembly, positive regulation of axon extension Cellular component cytosol, neuron projection, nucleus Molecular Function ATP binding, heat shock protein binding, protein serine/threonine kinase activity, zinc ion binding

  7. How does the actin cytoskeleton affect nervous system development? neuron pathfinding! http://www3.utsouthwestern.edu/psychlab/cowan/

  8. LIMK1 regulates actin cytoskeleton organization in hippocampus WT KO LIMK1 Meng, Y., Zhang, Y., Tregoubov, V., Janus, C., Cruz, L., Jackson, M., Lu, W.Y., MacDonald, J.F., Wang, J.Y., Falls, D.L., and Jia, Z. (2002). Neuron 35, this issue, 121–133.

  9. How does LIMK1 interact with other proteins? Image from: String Interaction Network 9.0

  10. Proteins expressed in human brain tissue Image from: String Interaction Network 9.0

  11. LIMK1 - binding domains

  12. Binding domains of interacting proteins SSH1 CLF1 PAK4 PAK1 Rac1 Images from PFAM

  13. Main hypothesis: Deletion of LIMK1 alters actin cytoskeleton organization of parietal neurons. Experiment 1: Establish where LIMK1 and interacting proteins localize in parietal neurons Experiment 2: Establish the role of cofilin in actin cytoskeleton organization in parietal neurons

  14. Model Organism http://adasperdown.blogspot.com/2012/02/mouse-remorse.html

  15. Homologs of LIMK1 Generated using TCoffee

  16. Protein interaction in humans Image from: String Interaction Network 9.0

  17. Protein interactions in mus musculus Image from: String Interaction Network 9.0

  18. Experiment 1 Question: How does LIMK1 and its interacting proteins localize in parietal neurons? Method: 1. RNAi to knockout LIMK1 (WS phenotype) 2. In LIMK1 WT and KO mice: Immunofluorescence - GFP (determine localization) Microarray (determine expression) http://anthropology.net/2008/02/29/differences-of-gene-expression-between-human-populations/microarray/ http://www.wadsworth.org/cores/alm/gallery.htm Microarray (determine expression)

  19. Cofilin - LIMK1 interaction Inactivates 1. 2. inhibition of neurite transport and synaptic loss in many cognitive disorders X LIMK1 CFL1 Activates http://www.ncbi.nlm.nih.gov/pubmed/16230460

  20. Previous studies have shown decreased spine area and length of postsynaptic density in hippocampus when LIMK1 is deleted (via effect on actin filament dynamics through hyperactivation of cofilin) Samiere PD, Bamburg JR. Head, neck, and spines: a role for LIMK-1 in the hippocampus. Neuron. 2002;35:3-5/

  21. Experiment 2 Question: What is the role of cofilin in actin cytoskeleton organization in parietal neurons? Method: 1. RNAi (generate KO LIMK1 mice) 2. In LIMK1 WT and KO: Immunohistochemistry- (determine phosphorylation (inactivation) of cofilin) Immunofluorescence - GFP (determine localization) Microarray (determine expression) http://www.jbc.org/content/282/32/23491/F5.expansion.html http://www.sciencedirect.com/science/article/pii/S0169328X0200445X

  22. Future research Can LIMK1 be linked to anxiety in WS patients? Chemical screen - regulate cofilin activation http://www.kcl.ac.uk/depsta/biomedical/randall/methods/im-fluo.html

  23. Sources Gungabissoon, R.A., and Bamburg, J.R. (2003). Regulation of growth cone actin dynamics by ADF/Cofilin. J. Histochem. Cytochem. 51, 411–420. http://www.braincenteramerica.com/visuospa.php Meng Y, Takahashi H, Meng J, Zhang Y, Lu G, Asrar S, Nakamura T, Jia Z. Regulation of ADF/cofilin phosphorylation and synaptic function by LIM-kinase. Neuropharmacology. 2004;47:746–754. Meng Y, Zhang Y, Tregoubov V, Janus C, Cruz L, Jackson M, Lu WY, MacDonald JF, Wang JY, Falls DL, and Jia Z. Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35: 121–133, 2002. Samiere PD, Bamburg JR. Head, neck, and spines: a role for LIMK-1 in the hippocampus. Neuron. 2002;35:3-5/ http://www.pdb.org/pdb/explore/explore.do?structureId=3S95

  24. Questions? http://www.wadsworth.org/cores/alm/gallery.htm

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