Departamento de Biología Celular and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universidad de Valencia, 46100 Burjassot, Spain.
Cell Stem Cell. 2010 Sep 3;7(3):367-79. doi: 10.1016/j.stem.2010.06.021.
Stem cell division can result in two sibling cells exhibiting differential mitogenic and self-renewing potential. Here, we present evidence that the dual-specificity kinase Dyrk1A is part of a molecular pathway involved in the regulation of biased epidermal growth factor receptor (EGFR) signaling in the progeny of dividing neural stem cells (NSC) of the adult subependymal zone (SEZ). We show that EGFR asymmetry requires regulated sorting and that a normal Dyrk1a dosage is required to sustain EGFR in the two daughters of a symmetrically dividing progenitor. Dyrk1A is symmetrically or asymmetrically distributed during mitosis, and biochemical analyses indicate that it prevents endocytosis-mediated degradation of EGFR by a mechanism that requires phosphorylation of the EGFR signaling modulator Sprouty2. Finally, Dyrk1a heterozygous NSCs exhibit defects in self-renewal, EGF-dependent cell-fate decisions, and long-term persistence in vivo, suggesting that symmetrical divisions play a role in the maintenance of the SEZ reservoir.
干细胞分裂可导致两个同胞细胞表现出不同的有丝分裂和自我更新潜能。在这里，我们提供的证据表明，双特异性激酶 Dyrk1A 是参与调节成年室下区（SEZ）分裂神经干细胞（NSC）后代中偏向性表皮生长因子受体（EGFR）信号的分子途径的一部分。我们表明，EGFR 不对称性需要受调控的分选，并且正常的 Dyrk1a 剂量是维持对称分裂祖细胞的两个子细胞中 EGFR 所必需的。Dyrk1A 在有丝分裂期间呈对称或不对称分布，生化分析表明，它通过一种需要 EGFR 信号调节剂 Sprouty2 磷酸化的机制来防止内吞作用介导的 EGFR 降解。最后，Dyrk1a 杂合性 NSCs 表现出自我更新、EGF 依赖性细胞命运决定以及体内长期持久性缺陷，表明对称分裂在 SEZ 库的维持中发挥作用。
