Mechanisms of Adrenal Lineage Development

项目摘要 分化细胞响应激素反馈的谱系转换尚未被描述。到 我们正在研究肾上腺皮质，它是由功能不同的同心层组成的 在出生后发育的两个亚门：外囊球状门（zG）和内囊束状门（zF）。这些层 具有独立的功能，并根据生理需求不断更新， 不连续的荷尔蒙反馈回路然而，它们的细胞起源、谱系关系和更新机制， 仍然知之甚少。已经提出，分化的zG细胞经历谱系转化为zF， 细胞使用zG特异性Cre表达的细胞命运作图和基因缺失研究证实了这一假设 而建立的谱系转换依赖于主转录调节因子类固醇生成因子1 （SF1）。这些发现表明肾上腺皮质带状化是谱系转换的结果， 为其他组织中的稳态细胞更新提供范例。该提案旨在定义蜂窝 以及使用谱系追踪、谱系诱导、基因 删除，基因稳定，激素和昼夜节律分析。具体来说，我们将描述 对修饰SF 1信号传导及其下游靶点的谱系转换和肾上腺稳态的影响， 包括经典的Wnt/β-连环蛋白信号通路和内源性肾上腺时钟。

Project Summary Lineage conversion of differentiated cells in response to hormonal feedback has yet to be described. To investigate this we are studying the adrenal cortex, which is composed of functionally distinct concentric layers that develop postnatally, the outer zona Glomerulosa (zG) and the inner zona Fasciculata (zF). These layers have separate functions and are continuously renewed in response to physiological demands regulated by discrete hormonal feedback loops. Their cellular origin, lineage relationship and renewal mechanism, however, remain poorly understood. It has been proposed that differentiated zG cells undergo lineage conversion into zF cells. Cell fate mapping and gene deletion studies using zG-specific Cre expression confirmed this hypothesis and established lineage conversion is dependent on the master transcriptional regulator Steroidogenic Factor 1 (SF1). These findings demonstrate that adrenocortical zonation results from lineage conversion and may provide a paradigm for homeostatic cellular renewal in other tissues. This proposal seeks to define the cellular and molecular mechanisms underlying lineage conversion using lineage-tracing, lineage-induction, gene deletion, gene stabilization, and hormonal and circadian analyses. Specifically, we will characterize the effect on lineage conversion and adrenal homeostasis of modifying SF1 signaling and its downstream targets, including the canonical Wnt/¿-catenin signaling pathway and the intrinsic adrenal clock.