DYRK1A roles in human neural progenitors

Jeremie Courraud ¹ Angélique Quartier ¹ Nathalie Drouot ¹ Irene Zapata- Bodalo ¹ Johan Gilet ¹ Alexandra Benchoua ² Jean-Louis Mandel ¹ Amélie Piton ^1*

• ¹ Université de Strasbourg, Strasbourg, France
• ² Istem, Evry, France

Mutations in DYRK1A represent one of the most prevalent monogenic causes of neurodevelopmental disorders (NDD), often associated with intellectual developmental disorder and autism spectrum disorder. DYRK1A encodes a dual-specificity kinase (tyrosine and serine/threonine) that plays a key role in various cellular processes and is a critical regulator of nervous system development. For the first time, we have characterized the DYRK1A interactome in human neural stem cells (hNSCs), identifying 35 protein partners involved in essential pathways such as cell cycle regulation and DNA repair. Notably, five of these interactors are components of the Anaphase-Promoting Complex (APC), and one is an additional ubiquitin ligase, RNF114 (also known as ZNF313), which is known to target p21. Many of these identified partners are also linked to other human NDD, and several others (e.g., DCAF7, GSPT1) may represent novel candidate genes for NDD. DYRK1A knockdown (KD) in hNSCs using siRNA revealed changes in the expression of genes encoding proteins involved in extracellular matrix composition and calcium binding (e.g., collagens, TGFβ2). While the majority of genes were downregulated following DYRK1A depletion, we observed an upregulation of early growth factors (EGR1, EGR3), as well as E2F2 and its downstream targets. Additionally, DYRK1A-KD led to a reduction in p21 protein levels, despite an increase in the expression of a minor transcript variant for this gene, and a decrease of ERK pathway activation.Together, the DYRK1A interactome in hNSCs and the gene expression changes induced by its depletion highlight the significant role of DYRK1A in regulating hNSCs proliferation. Although the effects on various growth signaling pathways may appear contradictory, the overall impact is a marked reduction in hNSCs proliferation. This research underscores the pivotal role of DYRK1A in neurodevelopment and identifies, among DYRK1A's protein partners and differentially expressed genes, potential novel candidate genes for NDD and promising therapeutic targets for DYRK1A syndrome.