成年哺乳动物大脑中，神经干细胞（NSCs）位于高度限制的生态位中，维持着产生整合进已有回路的新神经元的能力。成年神经元生成的减少与衰老和神经退行性疾病有关，而NSCs增殖和存活的失控被假设为胶质瘤的起因。因此，阐明NSCs为了增殖和产生新的后代所必须经历的调节激活的分子基础具有相当重要的意义。当前的研究已经确定了促进或限制NSCs激活的信号。然而，NSCs是否依赖外部信号以维持存活，或者是否由内在因素来建立存活的阈值仍然不清楚，尽管这方面的知识可能涉及到制定新的治疗策略的潜力。Kidins220（220千达因子与激酶D相互作用的底物）是一个对神经细胞生存和分化至关重要的通路效应器。它在癌症和神经系统和神经退行性疾病中发生剧烈变化，成为一个在人类疾病中具有重要功能的调节分子。在这里，我们发现Kidins220缺陷小鼠存在严重的神经生成缺陷和基于海马体的空间记忆障碍，伴随着神经干细胞死亡的增加和新形成神经元的高度丧失。在机制上，我们证明Kidins220依赖于AKT的激活可以对抗GSK3活性，从而阻止NSCs的凋亡作用。我们还展示了拥有Kidins220的NSCs可以在EGF的浓度较低条件下存活，而没有这种分子的NSCs无法存活。因此，Kidins220水平为成年NSCs在有且只有足够的促细胞因子的情况下存活设定了分子阈值，从而促使其生长和扩张。我们的研究确定了Kidins220作为感知生长因子可用性以维持成年神经生成的关键因子，揭示了一条可能有助于神经修复的分子联系。©2023年。作者们。

In the adult mammalian brain, neural stem cells (NSCs) located in highly restricted niches sustain the generation of new neurons that integrate into existing circuits. A reduction in adult neurogenesis is linked to ageing and neurodegeneration, whereas dysregulation of proliferation and survival of NSCs have been hypothesized to be at the origin of glioma. Thus, unravelling the molecular underpinnings of the regulated activation that NSCs must undergo to proliferate and generate new progeny is of considerable relevance. Current research has identified cues promoting or restraining NSCs activation. Yet, whether NSCs depend on external signals to survive or if intrinsic factors establish a threshold for sustaining their viability remains elusive, even if this knowledge could involve potential for devising novel therapeutic strategies. Kidins220 (Kinase D-interacting substrate of 220 kDa) is an essential effector of crucial pathways for neuronal survival and differentiation. It is dramatically altered in cancer and in neurological and neurodegenerative disorders, emerging as a regulatory molecule with important functions in human disease. Herein, we discover severe neurogenic deficits and hippocampal-based spatial memory defects accompanied by increased neuroblast death and high loss of newly formed neurons in Kidins220 deficient mice. Mechanistically, we demonstrate that Kidins220-dependent activation of AKT in response to EGF restraints GSK3 activity preventing NSCs apoptosis. We also show that NSCs with Kidins220 can survive with lower concentrations of EGF than the ones lacking this molecule. Hence, Kidins220 levels set a molecular threshold for survival in response to mitogens, allowing adult NSCs growth and expansion. Our study identifies Kidins220 as a key player for sensing the availability of growth factors to sustain adult neurogenesis, uncovering a molecular link that may help paving the way towards neurorepair.© 2023. The Author(s).