Sci. STKE, 6 June 2006
DOWN SYNDROME Down with NFAT Signaling?
Two independent groups obtained evidence linking dysregulation of nuclear factor of activated T cells (NFAT) signaling with Down syndrome. Down syndrome, most commonly associated with an extra copy of chromosome 21, is characterized by a constellation of traits that include mild to moderate mental retardation; neurological, skeletal, cardiovascular, and immunological abnormalities; muscle hypotonia; and enhanced sociability. The NFATc family of transcription factors, which are critical to development, reside in the cytoplasm in a phosphorylated form; they are dephosphorylated by calcineurin in response to calcium influx and translocate to the nucleus to activate target genes. Noting that mice lacking both Nfatc2 and Nfatc4 showed skull and jawbone abnormalities like those of people with Down syndrome, Arron et al. took a close look at mice lacking various Nfatc genes and found that they also displayed other features evocative of Down syndrome. Examination of the region of human chromosome 21 believed to contain genes responsible for the Down syndrome phenotype (the Down syndrome critical region, DSCR) revealed two potential regulators of NFAT signaling: DSCR1 (which encodes a calcineurin inhibitor) and DYRK1A (dual-specificity tyrosine-phosphorylation regulated kinase), which encodes a nuclear serine/threonine kinase. DYRK1A and DSCR1 synergistically inhibited NFAT-dependent transcription in cultured neurons. Moreover, DYRK1A, which phosphorylated NFATc4 and primed it for phosphorylation by glycogen synthase kinase 3 (GSK3), promoted NFATc4 export from the nucleus. Transgenic mice that overexpressed Dyrk1a and Dscr1 showed cardiovascular abnormalities consistent with their possible involvement in Down syndrome as well as cytoplasmic localization of endocardial NFATc1.
Gwack et al. identified the predominantly cytoplasmic DYRK2 in a genome-wide RNAi screen for regulators of NFAT signaling in Drosophila (which don't express NFAT but do have the regulatory pathway) by monitoring localization in S2R+ cells of a protein containing the NFAT1 regulatory domain linked to green fluorescent protein (NFAT-GFP). Overexpression of DYRK2 blocked nuclear translocation of NFAT-GFP in HeLa cells treated with thapsigargin (to increase cytoplasmic calcium), whereas depletion of endogenous DYRK1A enhanced NFAT1-GFP dephosphorylation and its nuclear localization. DYRK1A and DYRK2 directly phosphorylated NFAT and primed it for phosphorylation by GSK3 and CK1. The authors note the localization of DYRK1A and DSCR1 to the DSCR and the possible implications of NFAT dysregulation for Down syndrome. Epstein comments on both articles in a News & Views piece.
J. R. Arron, M. M. Winslow, A. Polleri, C.-P. Chang, H. Wu, X. Gao, J. R. Neilson, L. Chen, J. J. Heit, S. K. Kim, N. Yamasaki, T. Miyakawa, U. Francke, I. A. Graef, G. R. Crabtree, NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441, 595-600 (2006). [PubMed]
Y. Gwack, S. Sharma, J. Nardone, B. Tanasa, A. Iuga, S. Srikanth, H. Okamura, D. Bolton, S. Feske, P. G. Hogan, A. Rao, A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature 441, 646-650 (2006). [PubMed]
C. J. Epstein, Down's syndrome: Critical genes in a critical region. Nature 441, 582-583 (2006). [PubMed]
Citation: Down with NFAT Signaling? Sci. STKE 2006, tw190 (2006).
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