The Crabtree laboratory is located in the Beckman Center on the Stanford University Campus (see map) adjacent to the Fairchild Building and the Clark Center (BioX) and across Campus Drive from the Biology, Chemistry and Phyics Departments. We can be reached at 650-723-3685 or by fax at 650-723- 5158.
Mailing Address: Rm B211, Beckman Bldg. , 279 Campus Drive, Stanford CA 94305 Email:Crabtree@stanford.edu
How do cells perceive and respond to their environment? This was the question that inspired the origin of our lab and led to the elucidation of the NFAT signaling pathway that plays many essential roles in vertebrate organogenesis and development. Shown above is the growth cone of a neuron which responds to local guidance cues and uses Calcineurin/NFATc to transmit these cues to the nucleus. For more on this see Graef et al Cell 2003.
The developing leaflets of the heart valves (above) require reciprocal NFAT signaling between the tissue layers that will eventually produce the valves.NFATc1 is shown in green, calcineurin is in blue and nuclei in red. Notice that NFATc1 is nuclear only in the cells that will produce the valve. For more about this see Chang et al Cell Sept 3rd 2004.
Above is the branching pattern of the nerves carrying sensory information from the skin and muscles to the brain. Develoment of this precise pattern is dependent on calcineurin/NFAT signaling, but the way that NFAT signaling produces this complex morphology is unclear. more...
Signaling and Chromatin Regulation
As the pathways that carry information from the cell membrane to the nucleus are elucidated a paradox has became apparent: only about a dozen generic signaling pathways appear to be responsible for carrying all the information from the cell membrane to the nucleus to result in the development of the embyro and cellular responses to the environment.Where does the specificity of signaling then arise? At least part of the answer appears to be the preexisting chromatin context in which the signal is received. Inspired by work in yeast by the late Ira Herskowitz, several years ago we isolated a chromatin remodeling complex similar to the ATP-dependent yeast SWI/SNF complex and cloned the genes that encode the subunits of this complex...more
Designing Small Molecules to Explore Biologic Processes and for Therapeutic Purposes.
A goal of our laboratory is to develop methods to rapidly and reversibly regulate mammalian proteins that could be used like temperature-sensitive alleles in model organisms. We developed a Trojan Horse strategy that involves recruiting the steric bulk and surface area of endogenous proteins. For more on this see Gestwicki et al Science in press Oct 29th 2004...more...
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Gallo, E. M. et al. Calcineurin sets the bandwidth for discrimination of signals during thymocyte development. Nature 450, 731-5 (2007). Lessard, J. et al. An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 55, 201-15 (2007). Wu, J. I. et al. Regulation of dendritic development by neuron-specific chromatin remodeling complexes. Neuron 56, 94-108 (2007). Liu, K. J., Arron, J. R., Stankunas, K., Crabtree, G. R. & Longaker, M. T. Chemical rescue of cleft palate and midline defects in conditional GSK-3beta mice. Nature 446, 79-82 (2007). Heit, J. J. et al. Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function. Nature 443, 345-9 (2006). Arron, J. R. et al. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441, 595-600 (2006). Gestwicki J, Crabtree GR and Graef IA Harnessing Chaperones to Generate Potent Small Molecule Inhibitors of Amyloid Aggregation. Science, Oct 29, 2004 p 865-869, PDF or HTML For information from the popular press see BBC News, or Scientific American (PDF), or CNN News (PDF), or Chemical Engineering News, or HHMI Report, or ABC News Chang, CP, Neilson, J.R. Bayle, J.H., Gestwicki, J.E., Kuo, a. Stankunas, K. Graef, IA and Crabtree G.R. A Field of Calcineurin-NFAT signaling underlies heart valve morphogenesis, Cell Sept 3rd 2004. Note the cover design and the accompanying editorial. PDF or HTLM for the paper, PDF or HTML for the Editorial Rose RB, Pullen KE, Bayle JH, Crabtree GR, Alber
T.Biochemical and structural basis for partially redundant
enzymatic and transcriptional functions of DCoH and DCoH2. Parsons SA, Millay DP, Wilkins BJ, Bueno OF, Tsika
GL, Neilson JR, Liberatore CM, Yutzey KE, Crabtree GR, Tsika RW,
Molkentin JD. Genetic loss of calcineurin blocks mechanical overload-induced
skeletal muscle fiber type switching but not hypertrophy. Brand M, Ranish JA, Kummer NT, Hamilton J, Igarashi
K, Francastel C, Chi TH, Crabtree GR, Aebersold R, Groudine M. Dynamic
changes in transcription factor complexes during erythroid differentiation
revealed by quantitative proteomics. Neilson JR, Winslow MM, Hur EM, Crabtree GR. Stankunas et al. Condtional Protein Alleles Using Knock-in Mice and a Chemical Inducer of Dimerization Mol Cell Dec 12, 1615-1624, 2003.HTML PDF Graef I.A. et al Neurotrophins and netrins require calcineurin/NFAT signaling to stimulate outgrowth of embryonic axons.Cell. 2003 May 30;113(5):657-70. HTML PDF Chi et al. Sequential roles of Brg, the ATPase subunit of BAF chormatin remodeling complexes in thymocyte development. Immunity 2003, 169-182 HTML PDF Chang CP, et al. Sonographic staging of the developmental status of mouse embryos in utero.Genesis. 2003 May;36(1):7-11. HTML Olave I, et al Identification of a polymorphic, neuron-specific chromatin remodeling complex.Genes Dev. 2002 Oct 1;16(19):2509-17. HTML PDF Sheridan et al. Protein kinase A negatively modulates the nuclear accumulation of NF-ATc1 by priming for subsequent phosphorylation by glycogen synthase kinase-3.J Biol Chem. 2002 Dec 13;277(50):48664-76 HTML Diehn M, et al .Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation.Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11796-801. HTML Chi et al.Reciprocal regulation of CD4/CD8 expression by SWI/SNF-like BAF complexes.Nature. 2002 Jul 11;418(6894):195-9. HTML PDF Bayle et. al. Hyperphenylalaninemia and impaired glucose tolerance in mice lacking the bifunctional DCoH gene.J Biol Chem. 2002 Aug 9;277(32):28884-91HTML Rando OJ, et al. Phosphatidylinositol-dependent actin filament binding by the SWI/SNF-like BAF chromatin remodeling complex.Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2824-9. HTML Graef IA, et al. Signals transduced by Ca(2+)/calcineurin and NFATc3/c4 pattern the developing vasculature.Cell. 2001 Jun 29;105(7):863-75 HTML PDF Biggar SR, and Crabtree GR. Cell signaling can direct either binary or graded transcriptional responses.EMBO J. 2001 Jun 15;20(12):3167-76 HTML PDF Graef IA, et al. Evolutionary relationships among Rel domains indicate functional diversification by recombination.Proc Natl Acad Sci U S A. 2001 May 8;98(10):5740-5 HTML Graef IA, et al. L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons.Nature. 1999 Oct 14;401(6754):703-8 HTML PDF |
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Aramburu
J, Heitman J, Crabtree GR. Calcineurin: a central controller
of signalling in eukaryotes. Winslow MM, et al. Calcium signalling in lymphocytes.Curr Opin Immunol. 2003 Jun;15(3):299-307. HTML Rando OJ, et al. Second messenger control of chromatin remodeling. Nat Struct Biol. 2003 Feb;10(2):81-3. HTML Olave IA, et al Nuclear actin and actin-related
proteins in chromatin remodeling. Crabtree GR, Olson EN. NFAT signaling: choreographing
the social lives of cells. Graef IA, et al. NFAT signaling in vertebrate development. Curr Opin Genet Dev. 2001 Oct;11(5):505-12 HTML Chi TH, and Crabtree GR. Perspectives: signal transduction. Inositol phosphates in the nucleus.Science. 2002 Mar 17;287(5460):1937-9 HTML Crabtree GR. Calcium, calcineurin, and the control
of transcription. Stewart S, Crabtree GR. Transcription. Regulation
of the regulators. |