title: DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome.
abstract: 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.
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Jianxing
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Su
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Ning
authors.initials: N
authors.lastname: Xin
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Marta A
authors.initials: MA
authors.lastname: Gaertig
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.|Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Roger H
authors.initials: RH
authors.lastname: Reeves
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322; xli2@emory.edu sli@emory.edu.
authors.forename: Shihua
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322; xli2@emory.edu sli@emory.edu.|Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510631, China.
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D002479:Inclusion Bodies / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000097603:Dyrk Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C000626847:Dcaf7 protein, mouse; C490758:Hap1 protein, mouse
keywords: DYRK1A; Dcaf7; Down syndrome; Hap1; WDR68