Dlk1 dosage regulates hippocampal neurogenesis and cognition.
Dlk1 dosage regulates hippocampal neurogenesis and cognition.
复制标题
DOI：
10.1073/pnas.2015505118
复制
发表时间：
2021-03-16
影响因子：
11.1
通讯作者：
Ferrón SR
中科院分区：
文献类型：
--
作者：
Montalbán-Loro R;Lassi G;Lozano-Ureña A;Perez-Villalba A;Jiménez-Villalba E;Charalambous M;Vallortigara G;Horner AE;Saksida LM;Bussey TJ;Trejo JL;Tucci V;Ferguson-Smith AC;Ferrón SR
在成人大脑中，新神经元的产生通常发生在两个位置：侧脑室壁的脑室下区(SVZ)和海马齿状回(DG)的颗粒下区(SGZ)。成年海马区的神经发生与认知功能有关，如学习、记忆和应激反应的恢复。印记基因在大脑中非常普遍，并具有成人和发育的重要功能。印记基因DLK1在亲本等位基因中的缺失表明DLK1是成年海马神经干细胞静止的关键介质。此外，Dlk1在大脑中对剂量非常敏感，水平的扰动会导致NSCs功能和认知表型受损。成人大脑中的神经发生产生了功能神经元，这些神经元整合到神经元回路中，调节神经的可塑性。终生持续的神经发生发生在海马齿状回的颗粒下带(SGZ)，并被认为参与了行为/认知过程，如记忆和疾病。基因组印记对大脑发育和正常行为至关重要，并例证了表观遗传状态如何调节基因组功能和基因剂量。虽然大多数基因都来自两个等位基因，但印记基因通常是从母系或父系遗传的染色体中表达的。在这里，我们表明，与其在非神经源性区域的典型印记相反，Delta-like Homolog 1(Dlk1)在SGZ中以双等位表达，并且两个亲本等位基因都是干细胞行为和正常成年海马神经发生所必需的。为了评估Dlk1基因在特定行为领域内的母系、父系和双等位遗传突变的影响，我们对Dlk1突变小鼠进行了一系列测试，以分离和评估Dlk1剂量对空间学习能力和焦虑特征的影响。重要的是，Dlk1水平的降低会触发特定的认知异常，这些异常会影响环境刺激中辨别差异的各个方面，强调了在这个神经源性利基中选择性地缺乏印记的重要性。
Generation of new neurons occurs normally in the adult brain in two locations: the subventricular zone (SVZ) in the walls of the lateral ventricles and the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus. Neurogenesis in the adult hippocampus has been implicated in cognitive functions such as learning, memory, and recovery of stress response. Imprinted genes are highly prevalent in the brain and have adult and developmental important functions. Genetic deletion of the imprinted gene Dlk1 from either parental allele shows that DLK1 is a key mediator of quiescence in adult hippocampal NSCs. Additionally, Dlk1 is exquisitely dosage sensitive in the brain with perturbations in levels resulting in impaired NSCs function and cognitive phenotypes. Neurogenesis in the adult brain gives rise to functional neurons, which integrate into neuronal circuits and modulate neural plasticity. Sustained neurogenesis throughout life occurs in the subgranular zone (SGZ) of the dentate gyrus in the hippocampus and is hypothesized to be involved in behavioral/cognitive processes such as memory and in diseases. Genomic imprinting is of critical importance to brain development and normal behavior, and exemplifies how epigenetic states regulate genome function and gene dosage. While most genes are expressed from both alleles, imprinted genes are usually expressed from either the maternally or the paternally inherited chromosome. Here, we show that in contrast to its canonical imprinting in nonneurogenic regions, Delta-like homolog 1 (Dlk1) is expressed biallelically in the SGZ, and both parental alleles are required for stem cell behavior and normal adult neurogenesis in the hippocampus. To evaluate the effects of maternally, paternally, and biallelically inherited mutations within the Dlk1 gene in specific behavioral domains, we subjected Dlk1-mutant mice to a battery of tests that dissociate and evaluate the effects of Dlk1 dosage on spatial learning ability and on anxiety traits. Importantly, reduction in Dlk1 levels triggers specific cognitive abnormalities that affect aspects of discriminating differences in environmental stimuli, emphasizing the importance of selective absence of imprinting in this neurogenic niche.
登录
查看更多内容
影响因子：
--
作者：
Bray, Sarah J.;Takada, Shuji;Harrison, Emma;Shen, Shing-Chuan;Ferguson-Smith, Anne C.
通讯作者：
Ferguson-Smith, Anne C.
影响因子：
64.5
作者：
Bonaguidi MA;Wheeler MA;Shapiro JS;Stadel RP;Sun GJ;Ming GL;Song H
通讯作者：
Song H
影响因子：
16.6
作者：
Berdugo-Vega, Gabriel;Arias-Gil, Gonzalo;Calegari, Federico
通讯作者：
Calegari, Federico
影响因子：
10.6
作者：
Bahi A;Mineur YS;Picciotto MR
通讯作者：
Picciotto MR
影响因子：
14.8
作者：
Ferron, Sacri R.;Andreu-Agullo, Celia;Farinas, Isabel
通讯作者：
Farinas, Isabel