DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

• Type of Material: Article
• Authors: Jianxing Xiang, Emory University; Su Yang, Emory University; Ning Xin, Emory University; Marta A. Gaertig, Emory University; Roger H. Reeves, Johns Hopkins University; Shihua Li, Emory University; Xiao-Jiang Li, Emory University
• Language: English
• Date: 2017-02-14
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2017, National Academy of Sciences.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1614893114
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 114
• Issue: 7
• Start Page: E1224
• End Page: E1233
• Grant/Funding Information: This work was supported by NIH Grants NS036232 and NS041449 (to X.-J.L.), AG031153 and NS0405016 (to S.L.), and DH038384 (to R.H.R.) and by National Natural Science Foundation of China Grant 91332206 (to X.-J.L.).
• Keywords: WDR68; HUMAN HOMOLOG; Science & Technology; STIGMOID BODY; DYRK1A; NEURONAL DIFFERENTIATION; CELL-CYCLE EXIT; CENTRAL-NERVOUS-SYSTEM; SYNDROME CRITICAL REGION; Science & Technology - Other Topics; Dcaf7; SUBCELLULAR-LOCALIZATION; TS65DN MOUSE MODEL; Hap1; Multidisciplinary Sciences; RAT-BRAIN; HUNTINGTIN-ASSOCIATED PROTEIN-1; Down syndrome
• Research Categories: Biology, Genetics

Abstract

All rights reserved. Huntingtin-associated protein 1 (Hap1) is known to be critical for postnatal hypothalamic function and growth. Hap1 forms stigmoid bodies (SBs), unique neuronal cytoplasmic inclusions of unknown function that are enriched in hypothalamic neurons. Here we developed a simple strategy to isolate the SB-enriched fraction from mouse brain. By analyzing Hap1 immunoprecipitants from this fraction, we identified a Hap1-interacting SB component, DDB1 and CUL4 associated factor 7 (Dcaf7)/WD40 repeat 68 (WDR68), whose protein level and nuclear translocation are regulated by Hap1. Moreover, we found that Hap1 bound Dcaf7 competitively in cytoplasm with dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein implicated in Down syndrome (DS). Depleting Hap1 promoted the DYRK1A-Dcaf7 interaction and increased the DYRK1A protein level. Transgenic DS mice overexpressing DYRK1A showed reduced Hap1-Dcaf7 association in the hypothalamus. Furthermore, the overexpression of DYRK1A in the hypothalamus led to delayed growth in postnatal mice, suggesting that DYRK1A regulates the Hap1-Dcaf7 interaction and postnatal growth and that targeting Hap1 or Dcaf7 could ameliorate growth retardation in DS.