Wang Hui, Maggard Ben, Zheng Huifei Sophia, Kang Yuan, Huang Chen-Che Jeff
Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA.
Aging Cell. 2025 Oct;24(10):e70169. doi: 10.1111/acel.70169. Epub 2025 Jul 12.
In both humans and mice, the adrenal gland is a sexually dimorphic organ, but the extent of this diversity throughout development remains unclear. Here, we analyzed the mouse adrenal gland transcriptome at postnatal days 0, 7, 15, 21, 28, 35, and 49 to uncover its transcriptomic trajectory. Sex-dependent differences, indicated by the number of differentially expressed genes, gradually increase over time. Two Y-linked genes are consistently expressed in male adrenal glands, suggesting that factors beyond sex hormones may contribute to adrenal sexual dimorphism. Genes involved in steroidogenesis, cholesterol synthesis, and catecholamine synthesis exhibit sex- and age-dependent differential expression. Weighted gene co-expression network analysis (WGCNA) identified many genes with known zone-specific adrenal expression, including Akr1c18, Pik3c2g, Cyp2f2, Dhcr24, Thrb, and Spp1, clustering within the same module. FRZB, a WNT inhibitor, was also part of this module, exhibiting sex- and age-dependent expression. Immunostaining confirmed that FRZB is specifically expressed in the inner cortex, aligning with other inner cortex markers. Additionally, heatmap analysis revealed that many WNT downstream genes show age-dependent increases in expression in males, corresponding to progressively lower Frzb levels, suggesting a regulatory role for Frzb in adrenal sexual dimorphism. Furthermore, collagen-related genes were highlighted in the clustered heatmap of all differentially expressed genes due to their gradual decrease in expression over time. These observations suggest that this comprehensive dataset not only enhances our understanding of adrenal development and sexual dimorphism, aids in identifying novel marker genes for specific adrenal cell types, but also holds potential for contributing to aging research.
在人类和小鼠中，肾上腺都是一个具有性别二态性的器官，但在整个发育过程中这种差异的程度仍不清楚。在这里，我们分析了出生后第0、7、15、21、28、35和49天的小鼠肾上腺转录组，以揭示其转录组轨迹。由差异表达基因数量所表明的性别依赖性差异随时间逐渐增加。两个Y连锁基因在雄性肾上腺中持续表达，这表明除性激素外的其他因素可能导致肾上腺的性别二态性。参与类固醇生成、胆固醇合成和儿茶酚胺合成的基因表现出性别和年龄依赖性的差异表达。加权基因共表达网络分析（WGCNA）鉴定出许多已知在肾上腺特定区域表达的基因，包括Akr1c18、Pik3c2g、Cyp2f2、Dhcr24、Thrb和Spp1，它们聚集在同一模块中。WNT抑制剂FRZB也是该模块的一部分，表现出性别和年龄依赖性表达。免疫染色证实FRZB在内皮质中特异性表达，与其他内皮质标记物一致。此外，热图分析显示，许多WNT下游基因在雄性中的表达随年龄增加，这与Frzb水平逐渐降低相对应，表明Frzb在肾上腺性别二态性中起调节作用。此外，在所有差异表达基因的聚类热图中，胶原蛋白相关基因因其表达随时间逐渐下降而被突出显示。这些观察结果表明，这个综合数据集不仅增进了我们对肾上腺发育和性别二态性的理解，有助于识别特定肾上腺细胞类型的新型标记基因，而且在衰老研究方面也具有潜在贡献。
