Abstract
Overexpression of the Dual-specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) gene contributes to the retardation, craniofacial anomalies, cognitive impairment, and learning and memory deficits associated with Down Syndrome (DS). DCAF7/HAN11/WDR68 (hereafter WDR68) binds DYRK1A and is required for craniofacial development. Accumulating evidence suggests DYRK1A-WDR68 complexes enable proper growth and patterning of multiple organ systems and suppress inappropriate cell growth/transformation by regulating the balance between proliferation and differentiation in multiple cellular contexts. Here we report, using engineered mouse C2C12 and human HeLa cell lines, that WDR68 is required for normal levels of DYRK1A. However, Wdr68 does not significantly regulate Dyrk1a mRNA expression levels and proteasome inhibition did not restore DYRK1A in cells lacking Wdr68 (Δwdr68 cells). Overexpression of WDR68 increased DYRK1A levels while overexpression of DYRK1A had no effect on WDR68 levels. We further report that WDR68 is similarly required for normal levels of the closely related DYRK1B kinase and that both DYRK1A and DYRK1B are essential for the transition from proliferation to differentiation in C2C12 cells. These findings reveal an additional role of WDR68 in DYRK1A-WDR68 and DYRK1B-WDR68 complexes.
Highlights
Birth defects are among the leading causes of infant mortality
We examined the level of Dual-specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) in NT1 control cells and found that the level of DYRK1A is significantly higher in Differentiation Medium (DM) than growth medium (GM) (Fig 1A and 1A”, compare lane 3 to lane 1, p
WDR68 is required for normal levels of DYRK1A and DYRK1B
Summary
Birth defects are among the leading causes of infant mortality. Cleft lip with or without cleft palate (CL/P) affects 1 in 589 births [1]. Many craniofacial syndromes are caused by defects in signaling pathways. The DCAF7/HAN11/WDR68 (hereafter WDR68) gene is linked to CL/P [2] and required for Endothelin-1 (EDN1) signaling [3]. Defects in EDN1 signaling cause Auriculocondylar syndrome [4,5,6]. Down Syndrome (DS) affects 1 in 691 births [1]. Overexpression of the Dual-specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) gene contributes to the retardation, cognitive impairment, and learning and memory deficits associated with DS [7,8,9,10]. Human DYRK1A haploinsufficiency causes microcephaly [11,12,13].
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