Mechanisms of Adrenal Lineage Development

项目摘要 分化细胞对激素反馈反应的谱系转换尚未被描述。至 为此，我们正在研究肾上腺皮质，它由功能不同的同心层组成。 出生后发育的外肾带(Zg)和内束带(Zf)。这些层 具有不同的功能，并不断更新，以响应由 离散的荷尔蒙反馈循环。然而，它们的细胞起源、谱系关系和更新机制， 人们对此仍然知之甚少。有研究认为，分化后的ZG细胞经历了向ZF的谱系转化。 细胞。使用zg特异性Cre表达的细胞命运图谱和基因缺失研究证实了这一假设 已建立的谱系转换依赖于主要转录调节因子类固醇生成因子1 (SF1)。这些发现表明，肾上腺皮质分区是血统转换的结果，并可能 为其他组织的动态平衡细胞更新提供范例。这项提案试图定义蜂窝 以及利用谱系追踪、谱系诱导、基因 缺失、基因稳定、荷尔蒙和昼夜节律分析。具体地说，我们将描述这种影响 关于修饰SF1信号及其下游靶点的谱系转换和肾上腺动态平衡 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.