A Dual Role of Activin-like kinase 5 (ALK5)-mediated TGF Beta Signaling in Adult Neurogenesis

激活素样激酶 5 (ALK5) 介导的 TGF Beta 信号转导在成人神经发生中的双重作用

• 批准号: 10679216
• 负责人: Kierra Ware
• 金额: $ 4.09万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679216
• 关键词: Activins; Adult; Affect; Animal Model; Anxiety; Astrocytes; Brain; Cell Lineage; Cells; Central Nervous System; Central Nervous System Diseases; Chronic; Cognitive; Data; Development; Embryo; Emotional; Genes; Goals; Hippocampus; Homeostasis; In Vitro; Knock-out; Knockout Mice; Label; Ligands; Maps; Mediating; Memory; Mental Depression; Microglia; Migration Assay; Modeling; Molecular; Morphology; Mus; Neural Inhibition; Neurons; Oncogenes; Pathway interactions; Pattern; Perinatal; Phenotype; Phosphotransferases; Play; Process; Proliferating; Prosencephalon; Protocols documentation; Regulation; Reporter; Role; Signal Pathway; Signal Transduction; Site; Sorting; Specificity; TGF-beta type I receptor; Tamoxifen; Testing; Therapeutic; Time; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Vertebral column; adult neurogenesis; cell type; cognitive function; density; dentate gyrus; forgetting; functional outcomes; in vivo; inhibitor; insight; lateral ventricle; learning outcome; migration; mouse model; neonatal mice; nerve stem cell; nervous system disorder; nestin protein; neurite growth; neuroblast; neurodevelopment; neurogenesis; neuron development; novel; pharmacologic; receptor; repaired; single-cell RNA sequencing; stem cell migration; stem cell population; stem cell proliferation; transcriptomics

Project Summary New neurons are added in the adult mammalian brain by a process known as adult neurogenesis and adult neurogenesis is a key player in functional outcomes for learning and memory. One of the two known niches of adult neurogenesis is the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus. It is known that TGF-β signaling is crucial for neurogenesis during development while its role in adult neurogenesis remains unclear. Due to the lethal phenotype in early neonatal mice of the global TGF-β knockout mice, the precise role of TGF-β signaling in adult neurogenesis has been challenging to study. Chronic delivery of TGF-β in vivo inhibits neurogenesis; however, inhibition of TGF-β signaling via knockout of the type I receptor (Alk5) in mature and immature neurons also leads to compromised adult neurogenesis. Additionally, pharmacological modulation of TGF-β signaling in previous studies affect multiple cells types including neurons and microglia which are known to have an indirect role in regulating adult neurogenesis. Therefore, to understand the precise autonomous requirement of TGF-β signaling in the process of adult neurogenesis during different stages such as proliferation, differentiation, maturation, and migration, adult neural stem cell specific and inducible gene modulation models are needed. To circumvent these challenges in the field, we have generated NSC- specific TGF-β receptor type I (Alk5) or type II (TβRII) inducible knockout (iKO) mice which allows us to more specifically investigate how this signaling pathway affects adult NSCs and downstream progeny. Preliminary data from our lab shows in vitro pharmacological inhibition of TGF-β signaling with SB-431542 increases the proliferation of adult neural stem cell (NSCs) while treatment with TGF-β inhibits the proliferation. This implicates TGF-β signaling in playing an inhibitory role in the proliferation of adult NSCs. Additionally, our preliminary in vivo data from NestincreER-Alk5 iKO mice suggests TGF-β signaling is important for the maturation and migration of NSCs in the SGZ. We, therefore, hypothesize a dual role of TGF-β signaling in the neurogenic cascade which inhibits the proliferation of NSCs while simultaneously supporting maturation and migration in immature and mature neurons. The goal of this current study is to determine the precise functions and mechanisms of TGF-β signaling in regulation of adult neurogenesis through different stages and identify distinct target genes in each process. Although previous studies provide evidence of TGF-β signaling influencing adult neurogenesis, there are conflicting results throughout the field as TGF-β signaling is known to act in a highly context-dependent manner. With the specificity of our in vivo mouse models, this proposal will provide novel insight on the cellular and mechanistic processes involved with adult neurogenesis.

项目摘要 通过称为成人神经发生的过程和成人 神经发生是学习和记忆功能结果的关键参与者。两个已知的壁ni 成年神经发生是海马中齿状回（DG）的亚颗粒区（SGZ）。我们都知道 TGF-β信号传导对于发育过程中的神经发生至关重要，而其在成年神经发生中的作用仍然存在 不清楚。由于全球TGF-β敲除小鼠的早期新生小鼠的致命表型，精确作用 成人神经发生中TGF-β信号传导的研究挑战。长期递送TGF-β体内抑制 神经发生；但是，通过成熟和成熟的I型受体（ALK5）敲除抑制TGF-β信号传导 未成熟的神经元还导致成年神经发生受损。另外，药物调制 先前研究中的TGF-β信号传导影响多种细胞类型，包括神经元和小胶质细胞，这些类型已知 在调节成人神经发生中具有间接作用。因此，了解精确的自主 TGF-β信号在不同阶段（例如增殖）中的成人神经发生过程中的要求 分化，成熟和迁移，成年神经元干细胞特异性和诱导基因调节模型 需要。为了避免该领域的这些挑战，我们已经产生了NSC-特异性TGF-β受体类型 I（ALK5）或II型（TβRII）诱导型敲除（IKO）小鼠，这使我们能够更具体地研究了这一点 信号通路会影响成年NSC和下游后代。我们实验室的初步数据显示了体外 用SB-431542对TGF-β信号传导的药理抑制会增加成人神经茎的增殖 用TGF-β处理时细胞（NSC）抑制增殖。这种含义TGF-β信号在播放 抑制在成人NSC的增殖中的作用。此外，我们的初步体内数据来自Nestincreer-Alk5 IKO小鼠表明TGF-β信号传导对于SGZ中NSC的成熟和迁移很重要。我们， 因此，假设TGF-β信号在神经源性级联反应中的双重作用，该级联抑制了增殖 NSC的同时支持未成熟和成熟神经元中的成熟和迁移。目标 这项当前的研究是确定TGF-β信号传导在调节中的精确功能和机制 成人神经发生通过不同的阶段，并在每个过程中鉴定出不同的靶基因。虽然以前 研究提供了TGF-β信号传导的证据影响成人神经发生，结果存在冲突 已知通过TGF-β信号传导以高度上下文依赖性的方式起作用。具有特异性 在我们的体内鼠标模型中，该建议将提供有关细胞和机械过程的新见解 与成人神经发生有关。