The role of hormones in the development of the adrenal gland

Abstract

The adrenal cortex, a crucial endocrine gland, is comprised of three distinct regions: the zona glomerulosa, zona fasciculata, and zona reticularis (referred to as the X-zone in mice). This organ plays a critical role in maintaining adult homeostasis by generating steroid hormones. In order to meet the hormonal needs for steroid production, it has the ability to naturally replace aging cells. The innermost zone's cells are considered the aged cell population, which ultimately undergoes apoptosis. The factors influencing the fate of this aged cell population remain incompletely understood. My dissertation aims to address three fundamental questions: 1) What factors affect the aged cell population's fate? 2) What are the potential functions of the aged cell population? 3) What is the origin of the aged cell population? To address these questions, conditional knockout mice and transgenic mice were used in this thesis. In Chapter 2, we utilized tissue-specific gene editing techniques to eliminate the Ncor1 gene, which encodes the main corepressor in the thyroid hormone signaling pathway, in adrenocortical cells of the adrenal gland. The removal of Ncor1 was shown to delay cell regression in the adrenal inner cortex. In Chapter 3, we also applied tissue-specific gene editing methods to remove Dhcr24 in adrenocortical cells of the adrenal gland. In an earlier study, we had demonstrated that thyroid hormone upregulated cholesterol synthesis-related genes, with Dhcr24 being one of them. In this study, we found that Dhcr24 functioned as a key regulator of T3-mediated lipid accumulation. This inner cortex zone could potentially act as a reserve tissue for steroidogenesis. In Chapter 4, we studied the short- and long-term effects of glucocorticoids on adrenal gland function and development. RNA sequencing (RNA-seq) was conducted to identify early transcriptomic responses to the synthetic glucocorticoid dexamethasone (Dex) both in vitro and in vivo. Adrenocortical Y-1 cells exhibited a transient early response to Dex treatment in vitro. Moreover, the differentially expressed genes (DEGs) had minimal overlap between the 1-hour Dex-treated groups in vivo and in vitro. In Chapter 5, we employed a lineage tracing approach to investigate the role of Gli1 in the testis, another steroidogenesis organ. We successfully isolated cell-type-specific RNAs from heterogeneous tissue samples without the need for cell sorting. In Chapter 6, we performed a lineage tracing experiment to track Sonic hedgehog (Shh)-positive cells, which are progenitor cells, in post-weaning mice, revealing that the adrenal cortex undergoes replacement approximately every three months. Shh-positive cells reached the inner cortex, with a small portion becoming inner cortex marker-positive cells.