Understanding the developmental progression of subpallial neural progenitor cells

项目摘要 胚胎的端脑腹侧，即腭下区，是许多脑结构的发育起源 和细胞群如基底神经节和皮质中间神经元。这些结构和细胞群 对高级大脑功能至关重要，并且通常与神经精神疾病有关， 精神分裂症自闭症和毒瘾因此，更好地了解腹侧端脑发育 不仅能增进我们对大脑发育和大脑功能的理解， 神经系统紊乱在端脑腹侧产生的所有神经元和神经胶质都是 外膜下神经祖细胞（NPC），其在此广泛地包括已知的多能干细胞/祖细胞。 作为顶端祖细胞（AP）和谱系限制的传递放大细胞，称为基底或中间 祖细胞（BP）。由于对哺乳动物大脑发育过程中NPC的研究主要集中在 皮层，相对较少的是知道的步骤，发展进程的下苍白球NPC和 尽管很明显，覆盖层下的NPC必须具有独特的特征， 是它们独特的细胞输出的基础（就细胞数量和细胞类型而言）。本申请的目的是 探讨控制苍白球下膜发育进程的细胞和分子机制， 的npc最近，通过分析缺乏Tead 1和Tead 2的条件性敲除小鼠品系， Hippo通路的转录因子--一种对肿瘤的发生、发展 和跨物种的大多数组织再生，我们发现TEAD转录因子是新的， 调节器的发展进程的subpallial NPC;他们独特地调节subpallial，但不是 苍白球（皮质），NPC和行动通过海马通路依赖和非依赖机制。中央 这一建议的假设是，TEAD调节苍白球下NPC的发育进程， 双重作用模式：在AP中，TEAD与雅普/TAZ相互作用以维持AP状态;然而，在BP中，TEAD 与INSM 1相互作用以抑制AP状态并促进发育进展。具体而言是 拟开展的研究将：（1）通过使用各种基因修饰技术， 小鼠模型，（2）确定TEAD是否通过INSM 1在皮层下基底祖细胞中起作用，以及（3）确定 TEAD通过转录机制调节皮层下NPC。拟定研究 期望扩大我们的知识的机制，独特的调节发展进程， 并提高我们对一个重要的信号通路-Hippo通路的理解。

Project Summary The embryonic ventral telencephalon, the subpallium, is the developmental origin of numerous brain structures and cell populations such as the basal ganglia and cortical interneurons. These structures and cell populations are critical for higher brain functions and are often causally involved in neuropsychiatric disorders such as schizophrenia, autism, and drug addiction. Thus, a better understanding of ventral telencephalon development will not only improve our understanding of brain development and brain function but also advance treatments of nervous system disorders. All neurons and glia generated in the ventral telencephalon are descendants of subpallial neural progenitor cells (NPCs), which here broadly include multipotent stem/progenitor cells known as apical progenitors (APs) and lineage-restricted transit-amplifying cells known as basal or intermediate progenitors (BPs). Because research on NPCs during mammalian brain development has focused on the cortex, comparatively little is known about the steps of the developmental progression of subpallial NPCs and the mechanisms involved, although it is evident that subpallial NPCs must possess unique features that underlie their distinct cellular outputs (in terms of cell number and cell type). The objective of this application is to investigate the cellular and molecular mechanisms that control the developmental progression of subpallial NPCs. Recently, by analyzing a conditional knockout mouse line lacking Tead1 and Tead2, which encode key transcription factors of the Hippo pathway—a signaling pathway crucial for the development, tumorigenesis, and regeneration of most tissues across species, we found that the TEAD transcription factors are novel regulators of the developmental progression of subpallial NPCs; they uniquely regulate subpallial, but not pallial (cortical), NPCs and act through Hippo pathway-dependent and -independent mechanisms. The central hypothesis of this proposal is that TEAD regulates the developmental progression of subpallial NPCs with a dual mode of action: in APs, TEAD interacts with YAP/TAZ to maintain the AP state; in BPs, however, TEAD interacts with INSM1 to repress the AP state and promote developmental progression. Specifically, the proposed study will: (1) dissect the role of TEAD in subpallium development by using various genetic modified mouse models, (2) determine whether TEAD acts through INSM1 in subpallial basal progenitors, and (3) define the transcriptional mechanism through which TEAD regulates subpallial NPCs. The proposed study is expected to expand our knowledge of the mechanisms that uniquely regulate the developmental progression of subpallial NPCs and improve our understanding of an important signaling pathway—the Hippo pathway.