Dyrk1a, a Goldilocks protein in embryonic development

About This Grant

Project Summary: Cells are sensitive to changes in DYRK1A (Dual-specificity tyrosine-regulated kinase 1A) dosage. Too much DYRK1A occurs with Down Syndrome since it is located within the critical region of chromosome 21. Too little DYRK1A is associated with DYRK1A Syndrome caused by loss of function variants of the gene. Both these syndromes are characterized by a range of birth defects including craniofacial differences. Such differences can pose immense medical and social burdens regardless of intellectual problems. Therefore, the goal of this work is to investigate how alterations of DYRK1A dosage affects face formation. Moreover, we aim to uncover the mechanisms through which changes in the levels of this protein influences developmental processes such as cell cycle, senescence, and cell survival. We propose to integrate experiments in a developmental model Xenopus laevis with Down Syndrome patient derived cells and human stem cells. In Aim 1 we will test the hypothesis that too much DYRK1A causes inappropriate levels of senescent cells which in turn contributes to orofacial differences. We will scrutinize senescence in the developing face of Xenopus embryos and attempt to ameliorate craniofacial malformations in embryos with excess Dyrk1a using anti- senolytics and other agents to reduce senescence. We will also test whether a reduction in DYRK1A can delay or prevent Down Syndrome patient derived fibroblasts from entering senescence. This work could have an enormous impact on Down Syndrome research. In Aim 2 we will test the hypothesis that a reduction in Dyrk1a results in the activation of the intrinsic apoptotic pathway which contributes to orofacial differences. We propose that Dyrk1a is protective in the embryo in that it maintains pathways necessary for cell survival which allows for proper growth and development. Here we will further scrutinize the role for Dyrk1a in cell survival in craniofacial tissues and human mesenchymal iPS cells. Further, we will attempt to rescue craniofacial malformations with antiapoptotic or pro-survival agents. This could present new treatment avenues for DYRK1A Syndrome. In Aim 3 we will work on building the DYRK1A interactome in development. The focus will be on one protein, Lzts2, which preliminary evidence indicates it indeed interacts with Dyrk1a during craniofacial development. We will test the hypothesis that Lzts2 is required for nuclear localization and cell cycle regulatory functions of Dyrk1a. In addition, we will also evaluate whether novel DYRK1A interactors uncovered in a proteomics screen in the Litovchick lab also interact with Dyrk1a in craniofacial development. Understanding DYRK1A interactors could present new ways to modulate the function and levels of DYRK1A in associated syndromes in humans. In summary, the proposed work brings together a developmental biologist and an expert in DYRK1A molecular biology to make major inroads into the roles of this multifunctional kinase during development. Our work also aims to test new methods to ameliorate craniofacial defects caused by altered DYRK1A dosage. Such methods could translate to the development of therapeutics that could be used in both DYRK1A and Down Syndromes.