Faculty Information

Diane Slusarski

Professor
Ph.D., Northwestern University 1993
246A BB
(319) 335-3229
diane-slusarski@uiowa.edu

http://www.biology.uiowa.edu/slusarskilab

Signal Transduction Mechanisms in Vertebrate Development and Disease

Development from a single cell to a multicellular organism requires a dynamic interaction of signal transduction networks. The continuous exchange of information between cells through both contact and diffusible molecules influences gene expression and cell behavior. Our research focuses on cell-cell signaling events that lead to intracellular calcium release. We integrate in vivo image analysis coupled with molecular-genetic tools to elucidate the role of calcium-dependent signaling networks critical in developmental processes such as body plan formation and organogenesis in the zebrafish. The zebrafish (danio rerio) model system for vertebrate developmental biology has many attributes including genetics, rapid development and translucent embryos.

We defined a class of Wnt signaling ligands that modulate intracellular calcium release and are investigating the mechanisms by which this Wnt/calcium class mediates its biological effect on the developing embryo. In zebrafish, the Wnt-5 product is maternally required and loss of Wnt-5 of function results in decreased activity of calcium-dependent regulatory pathways and as a consequence, increased β-catenin signaling. Later-stage calcium manipulation results in increased nuclear β-catenin and perturbation of organ laterality and vascularization. As inappropriate Wnt signaling has been associated with a high frequency of tumors, we are also investigating spontaneous tumor formation in genetic backgrounds that disrupt the function of Wnt/calcium class ligands.

Additionally, we have determined that the calcium release requires G-protein signaling. To identify potential intracellular regulators of calcium release dynamics, we are characterizing members of the regulators of G-protein signaling protein family. We have cloned and characterized a few members of the RGS family and find they have essential roles in sensory neuron and somite patterning.

Due to the remarkable conservation of developmental processes and mechanisms among vertebrates, we also use zebrafish as a model for human disease and test candidate genes.

Keywords: Wnt/calcium Signaling in Development, Organogensis, Neural Patterning and Disease using the Zebrafish Model System

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Selected Publications

L.Sang, J.J. Miller, K.C. Corbit, R. H. Giles, M.J. Brauer, E.A. Otto, L.M. Baye, X. Wen, S.J. Scales, M. Kwong, E.G. Huntzicker, M.K. Sfakianos, W. Sandoval, J.F. Bazan, P. Kulkami, F.R. Garcia-Gonzalo, A.D. Seol, J.F. O'Toole, S. Held, H.M. Reutter, W.S. Lane, M.A. Rafiq, A. Noor, M. Ansar, A. Radha, R. Devi, V.C. Sheffield, D.C. Slusarski, J.B. Vincent, D.A. Doherty, F. Hildebrandt, J.F. Reiter and P.K. Jackson. (2011). Mapping the Nephronophthisis-Joubert-Meckel-Gruber Protein Network Reveals Ciliopathy Disease Genes and Pathways. Cell, 145 (4): 513-528.

P.R. Pretorius, M.A. Aldahmesh, F.S. Alkuraya. V.C. Sheffield, D.C. Slusarski. (2011). Functional analysis of BBS3 A89V that results in non-syndromic retinal degeneration. Human Molecular Genetics, 20(8):1625-32.

CJ Westlake,LM Baye, MV Nachury, KJ Wright, KE Ervin, L Phu, C Chalouni, JS Beck, DS Kirkpatrick, D.C. Slusarski, VC Sheffield, RH Scheller,PK Jackson. (2011). Primary cilia membrane assembly is initiated by Rab11 and transport protein particle II (TRAPPII) complex-dependent trafficking of Rabin8 to the centrosome. Proc Natl Acad Sci U S A, 108(7):2759-64.

L. M. Baye, X. Patrinostro, S. Swaminathan, J. S. Beck, Y. Zhang, E. M. Stone, V. C. Sheffield, D.C. Slusarski. (2011). The N-terminal region of CEP290 restores vision in a zebrafish model of human blindness. Human Molecular Genetics, 20(8):1467-77.

H.Tao, J.R. Manak, L. Sowers, X. Mei, H. Kiyonari, T. Abe, N.S. Dahdaleh, T. Yang, S. Wu, S. Chen, M.H. Fox, C. Gurnett, T. Montine, T. Bird, L.G. Shaffer, J.A. Rosenfeld, J. McConnell, S. Madan-Khetarpal, E. Berry-Kravis, H. Griesbach, R.P. Saneto, M.P. Scott, D. Antic, J. Reed, R. Boland, H. El-Shanti, V.B. Mahajan, P.J. Ferguson, J.D. Axelrod, A. Lehesjoki, B. Fritzsch,D.C. Slusarski, J. Wemmie, N. Ueno and A.G. Bassuk. (2011). Mutations in PRICKLE orthologues cause seizures in flies, mice and humans. The American Journal of Human Genetics,88: 1-12.

I. Schneider, P.N. Schneider, S.W. Derry, S. Lin, L.J. Barton, T. Westfall and D.C. Slusarski. (2010). Zebrafish Nkd1 promotes Dvl degradation and is required for left-right patterning. Developmental Biology, 348(1):22-33.

S. Lin, L.M. Baye, T.A. Westfall and D.C. Slusarski. (2010). Wnt5b/Ryk Pathway Provides Directional Signals to Regulate Zebrafish Gastrulation Movement. The Journal of Cell Biology, 190(2): 263-78.

C. M. Freisinger, R.A. Fisher, and D.C. Slusarski. (2010). Regulator of G protein Signaling 3 Modulates Wnt5b Calcium Dynamics and Somite Patterning. PLoS Genetics, 6(7):e1001020.

D.Y. Nishimura, L.M. Baye, R. Perveen, C.C. Searby, A. Avila-Fernandez, I. Pereiro, C. Ayuso, D. Valverde, F.D. Manson, J. Urquhart, E.M. Stone, D.C. Slusarski, G.C. Black, V.C. Sheffield. (2010). Discovery and Functional Analysis of a Novel Retinitis Pigmentosa Gene, C2orf71. The American Journal of Human Genetics, 86: 1–10.

R. Ju, P. Cirone, S. Lin, H. Griesbach, D.C. Slusarski and C.M. Crews. (2010). Activation of the Planar Cell Polarity Formin DAAM1 Leads to Inhibition of Endothelial Cell Proliferation, Migration and Angiogenesis. Proc Natl Acad Sci U S A, 107: 6906-6911.

P.R. Pretorius, L.M. Baye, D.Y. Nishimura, C.C. Searby, K. Bugge, B. Yang, R.F. Mullins, E.M. Stone, V.C. Sheffield and D.C. Slusarski. (2010). Insights into non-syndromic forms of Bardet-Biedl Syndrome: Identification and functional analysis of vision specific BBS 3 (ARL6) Long Isoform. PLoS Genetics;6(3):e1000884.

S. Seo, L.M. Baye, N.P. Schulz, J.S. Beck, Q. Zhang, D.C. Slusarski, and V.C. Sheffield. (2010). BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proc Natl Acad Sci U S A, 107: 1488-1493.

Holloway BA, Gomez de la Torre Canny S, Ye Y, Slusarski DC, Freisinger CM, et al. (2009) A Novel Role for MAPKAPK2 in Morphogenesis during Zebrafish Development. PLoS Genetics, 5(3): e1000413.

A.V. Loktev, Q. Zhang, J.S. Beck, C.C. Searby, T.E. Scheetz, J.F. Bazan,D.C. Slusarski, V.C. Sheffield, P.K. Jackson, and M.V. Nachury. (2008). A BBSome Subunit Links Ciliogenesis, Microtubule Stability, and Acetylation. Developmental Cell, 15: 1–12. (Journal Cover).

A.G. Bassuk, R.H. Wallace, A. Buhr, A.R. Buller, Z. Afawi, M. Shimojo, S. Miyata, S. Chen, P. Gonzalez-Alegre, H. L. Griesbach, S. Wu, M. Nashelsky, E.K. Vladar, D. Antic, P. J. Ferguson, S. Cirak, T. Voit, M.P. Scott, J.D. Axelrod, C. Gurnett, A.S. Daoud, S. Kivity, M.Y. Neufeld, A. Mazarib, R. Straussberg, S. Walid, A.D. Korczyn, D.C. Slusarski , S.F. Berkovic, & H. I. El-Shanti. (2008). A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome. The American Journal of Human Genetics, 83 : 572–581.

P. Cirone, Y. Zhang, S. Lin, H. Greisbach, Y. Zhang, D.C. Slusarski, and C.M. Crews. (2008). A Role for Planar Cell Polarity Signaling in Angiogenesis. Angiogenesis, 11:347-360.

M.K. Tayeh, H.-J. Yen, J.S. Beck, C.C. Searby, T.A. Westfall, H. Griesbach, V.C. Sheffield and D. C. Slusarski. (2008). Genetic interaction between Bardet-Biedl syndrome genes and implications for limb patterning. Human Molecular Genetics, 17: 1956-1967.

C. M. Freisinger, I. Schneider, T.A. Westfall and D. C. Slusarski. (2008). Calcium dynamics integrated into signalling pathways that influence vertebrate axial patterning. Phil. Trans. R. Soc. B, 363: 1377-1385. (Journal Cover).

I. Schneider, D. W. Houston, M. R. Rebagliati, and D. C. Slusarski. (2008). Calcium fluxes in dorsal forerunner cells antagonize β-catenin and alter left-right patterning. Development, 135, 75-84.

M.V. Nachury, A.V. Loktev, Q. Zhang, C.J. Westlake, J. Peränen, A. Merdes, D.C. Slusarski, R.H. Scheller, J.F. Bazan, V.C. Sheffield, and P.K. Jackson. (2007). A Core Complex of BBS Proteins Cooperates with the GTPase Rab8 to Promote Ciliary Membrane Biogenesis. Cell, 129: 1201–1213. (Journal Cover).

D.C. Slusarski and F. Pelegri. (2007). Calcium signaling in vertebrate patterning and morphogenesis. Developmental Biology, 307: 1-13.

Y. Harada, C. Yokota, R. Habas, D.C. Slusarski, and X. He. (2007). Retinoic Acid-Inducible G Protein-Coupled Receptors Bind to Frizzled Receptors and May Activate Non-canonical Wnt Signaling. Biochemical And Biophysical Research Communications, 358: 968–975.

Y. Zhang, J. R. Yeh, A. Mara, R. Ju, J. Hines, P. Cirone, H.L. Greisbach, I. Schneider, D.C. Slusarski, S.A. Holley, and C.M. Crews. (2006). A Chemical Genetic Approach to the Mode of Action of Fumagillin. Chemistry and Biology , 13: 1001-1009. (Journal Cover).

A.P. Chiang, J.S. Beck, H-J Yen, M.K. Tayeh, T.E. Scheetz, R. Swiderski, D. Nishimura, T.A. Braun, K-Y Kim, J. Huang, K. Elbedour, R. Carmi, D.C. Slusarski, T.L. Casavant, E.M. Stone, and V.C. Sheffield. (2006). Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet–Biedl syndrome gene (BBS11). Proceedings of the National Academy of Sciences, 103(16):6287-92.

Yen, H-J., Tayeh, M.K., Mullins, R.F., Stone, E.M., Sheffield, V.C. and D. C. Slusarski. (2006). Bardet-Biedl Syndrome Genes are Important in Retrograde Intracellular Trafficking and Kupffer's Vesicle Cilia Formation. Human Molecular Genetics, 15: 667-77. (Journal Cover).

Slusarski, D. C. (2006). Dynamic Analysis Of Calcium Signaling In Animal Development. In: “Methods in Signal Transduction” Series, Analysis of Growth Factor Signaling in Embryos (ed. M. Whitman and A.K. Sater) CRC press LLC. 8, pp. 157-175.

Gingerich, J.L., Stolzmann, K., Westfall, T., Slusarski, D.C. and F. Pelegri. (2005) hecate, a zebrafish maternal effect gene, affects dorsal organizer induction and intracellular calcium transient frequency. Developmental Biology, 286:427-439.

Westfall, T. A., Twedt, J., Olberding, A., Brimeyer, R., Gladon, J., Furutani-Seiki, M. and Slusarski, D. C. (2003). Wnt-5/pipetail functions in vertebrate axis formation as a negative regulator of Wnt/Beta-catenin activity. The Journal of Cell Biology, 162: 889-898.

Westfall, T., Hjertos, B., and Slusarski, D.C. (2003). Mechanisms of Calcium Modulation underlying Dorsal-Ventral Patterning in Zebrafish. Developmental Biology, 259: 380-391.

Sheldahl, L., Slusarski, D.C., Pandur, P., Miller, J., Kuhl, M. and Moon, R. T. (2003). Overlapping Wnt/Ca²⁺ and Planar Cell Polarity Pathways: Dishevelled Activates Ca²⁺, PKC, and CamKII Signaling. The Journal of Cell Biology, 161:1-10.

Veeman, M., Slusarski, D.C., Kaykas, A., Hallagan, S. and Moon, R. T. (2003). Zebrafish Prickle, a modulator of non-canonical Wnt/Fz signaling, regulates gastrulation movements. Current Biology, 13:680-685.

Ahumada, A., Slusarski, D.C., Liu, X., Moon, R.T., Malbon, C.C. and H-y Wang. (2002). Signaling of Rat Frizzled-2 through Phosphodiesterase and Cyclic Guanosine 3', 5'-monophosphate. Science, 298: 2006-2010.

Liu, X., Liu, T., Slusarski, D.C., Yang-Snyder, J., Malbon, C., Moon, R., Wang, H-y. (1999). A Frizzled 2/b₂-Adrenergic Receptor Chimera Activates Wnt-Signaling and Differentiation of Mouse F9 Teratocarcinoma Cells to Primitive Endoderm In Response to Isoprenaline. Proceedings of the National Academy of Science, 96:14383-14388.

Slusarski, D.C., V. Corces. (2000). Calcium Imaging and Cell-Cell Signaling. In: Methods in Molecular Biology, Vol. 135: Developmental Biology Protocols. (eds. R.S. Tuan and C.W. Lo). Vol. I, Chapter 25. Humana Press, Inc., Totowa.

Slusarski, D.C., V. Corces, R. Moon. (1997). Interaction of a Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling. Nature, 390:410-413.

Slusarski, D.C., J. Yang-Snyder, W. Busa, R.T. Moon. (1997). Modulation of embryonic intracellular Ca²⁺ signaling by Wnt-5A. Developmental Biology, 182 :114-120. (Journal Cover ).