Mechanisms of Adrenal Lineage Development

描述(申请人提供)：分化细胞对荷尔蒙反馈的谱系转换尚未被描述。为了研究这一点，我们正在研究肾上腺皮质，它由出生后发育的功能不同的同心层组成，即外层的肾状带(ZG)和内层的束状带(ZF)。这些层具有不同的功能，并根据离散的荷尔蒙反馈环调节的生理需求而不断更新。然而，它们的细胞起源、谱系关系和更新机制仍然知之甚少。有研究认为，分化后的ZG细胞经历了向ZF细胞的谱系转化。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，并建立了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，肾上腺皮质分区是谱系转换的结果，可能为其他组织的动态平衡细胞更新提供了一种范例。这一建议试图通过谱系追踪、谱系诱导、基因缺失、基因稳定以及荷尔蒙和昼夜节律分析来确定谱系转换的细胞和分子机制。具体地说，我们将表征修改sf1信号及其下游靶点对谱系转换和肾上腺动态平衡的影响，包括规范的Wnt/β-catenin信号通路和肾上腺内源性时钟。

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.