Mechanisms of Adrenal Lineage Development

描述（由申请人提供）：尚未描述响应激素反馈的分化细胞的谱系转换。为了研究这一点，我们正在研究肾上腺皮质，它是由功能不同的同心层，出生后发展，外珠囊（zG）和内珠囊束（zF）。这些层具有独立的功能，并不断更新，以响应由离散的激素反馈回路调节的生理需求。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，并且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（SF 1）。这些研究结果表明，肾上腺皮质分区的结果从谱系转换，并可能提供一个范例，在其他组织的稳态细胞更新。该建议旨在使用谱系追踪、谱系诱导、基因缺失、基因稳定以及激素和昼夜节律分析来定义谱系转换的细胞和分子机制。具体而言，我们将描述修饰SF 1信号及其下游靶点（包括经典Wnt/β-catenin信号通路和内源性肾上腺时钟）对谱系转换和肾上腺稳态的影响。

DESCRIPTION (provided by applicant): 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/β-catenin signaling pathway and the intrinsic adrenal clock.