Craniofacial dysmorphology in Down Syndrome is caused by increased dosage of Dyrk1a and at least three other genes

Redhead, Yushi; Gibbins, Dorota; Lana-Elola, Eva; Watson-Scales, Sheona; Dobson, Lisa; Krause, Matthias; Liu, Karen; Fisher, Elizabeth; Green, Jeremy; Tybulewicz, Victor L. J.

doi:10.1101/2022.06.27.497841

Cited by 3 publications

(3 citation statements)

References 77 publications

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“…Although there is limited research specifically investigating the impact of DYRK1A gene loss on craniofacial development in whole animal models, we do know that the protein is important in the context of Down Syndrome and DYRK1A overexpression models. For example, in mouse models of Down Syndrome, the use of DYRK1A inhibitors or genetic knockout of DYRK1A has been shown to mitigate skull and jaw malformations in such models (McElyea et al, 2016; Redhead et al, 2023). Thus, decreased, or increased dosage of DYRK1A is detrimental to craniofacial development indicating that Dyrk1a plays a crucial role in the development of the face.…”

Section: Introductionmentioning

confidence: 99%

Dyrk1a is required for craniofacial development inXenopus laevis

Johnson,

Wahl,

Sesay

et al. 2024

Preprint

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Loss of function mutations in the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene are associated with craniofacial malformations in humans. Here we characterized the effects of deficient DYRK1A in craniofacial development using a developmental model, Xenopus laevis. Dyrk1a mRNA and protein was expressed throughout the developing head and was enriched in the branchial arches which contribute to the face and jaw. Consistently, reduced Dyrk1a function, using dyrk1a morpholinos and pharmacological inhibitors, resulted in orofacial malformations including hypotelorism, altered mouth shape, slanted eyes, and narrower face accompanied by smaller jaw cartilage and muscle. Inhibition of Dyrk1a function resulted in misexpression of key craniofacial regulators including transcription factors and members of the retinoic acid signaling pathway. Two such regulators, sox9 and pax3 are required for neural crest development and their decreased expression corresponds with smaller neural crest domains within the branchial arches. Finally, we determined that the smaller size of the faces, jaw elements and neural crest domains in embryos deficient in Dyrk1a could be explained by increased cell death and decreased proliferation. This study is the first to provide insight into why craniofacial birth defects might arise in humans with DYRK1A mutations.

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Section: Introductionmentioning

confidence: 99%

Dyrk1a is required for craniofacial development inXenopus laevis

Johnson,

Wahl,

Sesay

et al. 2024

Preprint

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“…Osteoblastic markers Osterix and Nestin are positively correlated with osteogenesis. Moreover, Nestin(+) cell clusters result in the formation of bone marrow osteoid islets with high angiogenesis levels [35,36]. In our mouse model, there was an increase in Osterix and Nestin-positive cells, and these cells were primarily located in the bone marrow rather than the bone resorption zone.…”

Section: Discussionmentioning

confidence: 88%

The Therapeutic Role of Hyperoside in Medial Meniscus Destabilization-Induced Osteoarthritis: A Study on Subchondral Bone Remodeling

Yang,

Chen,

Tang

et al. 2024

Preprint

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Background The process of subchondral bone remodelling plays an imperative role in the progressive development of OA. Hyperoside (Hyp) is a flavonoid, which has a wide range of pharmacological effects. This study aims to explore the effect of Hyp on the subchondral bone to elucidate the therapeutic role of Hyp in medial meniscus destabilization (DMM) induced OA.Methods Firstly, we conducted histological research(HE staining, Safranin-O/Fast Green and Toluidine blue staining, TRAP staining, IHC) and microCT to test the ability of Hyp on cartilage degeneration and abnormal subchondral microstructural changes in the DMM-induced osteoarthritic mouse model. Secondly, In the in vitro experiments, RAW264.7 cells were induced to osteoblasts in the presence of different concentrations of Hyp and osteoclasts were labelled by TRAP staining. MC3TC-E1 cells were used to perform osteoinduction experiments in Osteogenic Induction Media (OIM). Osteogenic activity was observed through Alizarin red S staining, and mineralisation activity was observed through ALP staining. Last, Finally, the effect of Hyp on NF-κB pathways was studied using Western blot and immunofluorescence.Results Hyp decreased cartilage degeneration and improved BV/TV and Tb.Th structural parameters. It also reduced the number of TRAP-positive osteoclasts, nestin cells, and osterix cells in the subchondral bone. Additionally, Hyp Inhibits osteoclast formation and enhanced alkaline phosphatase activity and mineralization. Furthermore, the NF-κB signalling pathway related to osteoclasts was inhibited.Conclusion These results indicate that Hyp has potential therapeutic value for OA by modulating osteoclastogenesis and osteoblastogenesis in the subchondral bone.

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“…Human DYRK1A is encoded in the Down Syndrome Critical Region (DSCR) in chromosome 21 (Galceran et al, 2003;Hämmerle et al, 2003) and higher expression of DYRK1A is responsible for most of the phenotypes including intellectual disability of Down syndrome patients (Altafaj et al, 2001). A role of DYRK1A has also been suggested in other pathological conditions observed in Down syndrome patients, such as earlier onset of Alzheimer disease (Branca et al, 2017;Kimura et al, 2007), type 2 diabetes (Shen et al, 2015;Wang et al, 2015), and craniofacial malformation (Blazek et al, 2015;McElyea et al, 2016;Redhead et al, 2023). In addition, recent studies suggest that DYRK1A is also involved in several other neurodevelopmental disorders including ADHD (Attention Deficit Hyperactivity Disorder) (Tian et al, 2019), ASD (Autism Spectrum Disorder) (De Rubeis et al, 2014;O'Roak et al, 2012;van Bon et al, 2016), and DYRK1A-haploinsufficiency syndrome (Courcet et al, 2012;Courraud et al, 2021;Duchon & Hérault, 2016).…”

Section: Introductionmentioning

confidence: 99%

Identification of FAM53C as a cytosolic-anchoring inhibitory binding protein of the kinase DYRK1A

Miyata

Nishida

2023

Preprint

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A protein kinase DYRK1A encoded in human chromosome-21 is the major contributor for multiple symptoms observed in Down syndrome patients. In addition, DYRK1A dysfunction has been associated with various neuronal disorders, including autism spectrum disorder and Alzheimer disease. Here we identified FAM53C as a novel suppressive binding partner of DYRK1A. FAM53C bound to the catalytic kinase domain of DYRK1A, whereas DCAF7/WDR68, the major known DYRK1A-binding protein, binds to its N-terminal domain. The binding of FAM53C inhibited the protein kinase activity of DYRK1A to itself and an exogenous substrate MAPT/Tau. FAM53C did not bind directly to DCAF7/WDR68, whereas DYRK1A tethered FAM53C and DCAF7/WDR68 by binding concurrently to both of them. DYRK1A possesses a nuclear localization signal and accumulates in the nucleus when overexpressed in cells. FAM53C induced cytoplasmic re-localization of DYRK1A and DCAF7/WDR68. FAM53C is thus a binding suppressor of DYRK1A, anchoring it in an inactive state in the cytoplasm. The results explain for the first time why endogenous DYRK1A is distributed in the cytoplasm in the normal brain tissues. FAM53C-dependent regulation of DYRK1A may play a significant role in gene expression modification caused by DYRK1A.

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Craniofacial dysmorphology in Down Syndrome is caused by increased dosage of Dyrk1a and at least three other genes

Cited by 3 publications

References 77 publications

Dyrk1a is required for craniofacial development inXenopus laevis

Dyrk1a is required for craniofacial development inXenopus laevis

The Therapeutic Role of Hyperoside in Medial Meniscus Destabilization-Induced Osteoarthritis: A Study on Subchondral Bone Remodeling

Identification of FAM53C as a cytosolic-anchoring inhibitory binding protein of the kinase DYRK1A

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