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

Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):E1224-E1233. doi: 10.1073/pnas.1614893114. Epub 2017 Jan 30.

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.

Keywords: DYRK1A; Dcaf7; Down syndrome; Hap1; WDR68.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Nucleus / metabolism
  • Down Syndrome / genetics
  • Down Syndrome / metabolism*
  • Dyrk Kinases
  • HEK293 Cells
  • Humans
  • Hypothalamus / metabolism
  • Inclusion Bodies / metabolism
  • Mice, Knockout
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • RNA Interference

Substances

  • Adaptor Proteins, Signal Transducing
  • Dcaf7 protein, mouse
  • Hap1 protein, mouse
  • Nerve Tissue Proteins
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases