Courraud Jeremie, Quartier Angélique, Drouot Nathalie, Zapata-Bodalo Irene, Gilet Johan, Benchoua Alexandra, Mandel Jean-Louis, Piton Amélie
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
Front Neurosci. 2025 Mar 13;19:1533253. doi: 10.3389/fnins.2025.1533253. eCollection 2025.
Mutations in (DYRK1A) represent one of the most prevalent monogenic causes of neurodevelopmental disorders (NDDs), 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 and study the consequences of DYRK1A depletion in human neural stem cells (hNSCs).
We identified 35 protein partners of DYRK1A 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 NDDs, and several others (e.g., DCAF7 and GSPT1) may represent novel candidate genes for NDDs. 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 and UNC13A). While the majority of genes were downregulated following DYRK1A depletion, we observed an upregulation of early growth factors (EGR1 and EGR3), as well as E2F2 and its downstream targets. In addition, 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 in 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 hNSC proliferation. Although the effects on various growth signaling pathways may appear contradictory, the overall impact is a marked reduction in hNSC 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 NDDs and promising therapeutic targets for DYRK1A syndrome.
双特异性酪氨酸磷酸化调节激酶1A（DYRK1A）突变是神经发育障碍（NDDs）最常见的单基因病因之一，常与智力发育障碍和自闭症谱系障碍相关。DYRK1A编码一种双特异性激酶（酪氨酸和丝氨酸/苏氨酸），在各种细胞过程中起关键作用，是神经系统发育的关键调节因子。
我们首次对DYRK1A相互作用组进行了表征，并研究了人神经干细胞（hNSCs）中DYRK1A缺失的后果。
我们鉴定出35个DYRK1A的蛋白质伙伴，它们参与细胞周期调控和DNA修复等重要途径。值得注意的是，其中五个相互作用蛋白是后期促进复合体（APC）的组成部分，一个是另一种泛素连接酶RNF114（也称为ZNF313），已知其靶向p21。许多已鉴定的伙伴也与其他人类NDDs相关，其他几个（如DCAF7和GSPT1）可能代表NDDs的新候选基因。使用小干扰RNA（siRNA）在hNSCs中敲低（KD）DYRK1A，揭示了编码参与细胞外基质组成和钙结合的蛋白质（如胶原蛋白、转化生长因子β2和UNC13A）的基因表达变化。虽然在DYRK1A缺失后大多数基因下调，但我们观察到早期生长因子（EGR1和EGR3）以及E2F2及其下游靶点上调。此外，尽管该基因的一个小转录变体表达增加，但DYRK1A-KD导致p21蛋白水平降低，且细胞外信号调节激酶（ERK）途径激活减少。
总之，hNSCs中的DYRK1A相互作用组及其缺失诱导的基因表达变化突出了DYRK1A在调节hNSC增殖中的重要作用。尽管对各种生长信号通路的影响可能看似矛盾，但总体影响是hNSC增殖显著减少。本研究强调了DYRK1A在神经发育中的关键作用，并在DYRK1A的蛋白质伙伴和差异表达基因中，鉴定出NDDs的潜在新候选基因以及DYRK1A综合征有前景的治疗靶点。
