School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore.
Department of Oral Biology and Biomedical Sciences, Faculty of Dentistry, MAHSA University, Bandar Saujana Putra, 42610, Jenjarom, Selangor, Malaysia.
Sci Rep. 2022 Jul 19;12(1):12286. doi: 10.1038/s41598-022-16289-x.
Progesterone receptor (PGR) is a member of the nuclear receptor superfamily of transcription factors. It is critical for mammary stem cells expansion, mammary ductal branching and alveologenesis. The transcriptional activity of PGR is mainly mediated by activation functions AF1 and AF2. Although the discovery of AF1 and AF2 propelled the understanding of the mechanism of gene regulation by nuclear receptors, their physiological roles are still poorly understood. This is largely due to the lack of suitable genetic models. The present study reports gain or loss of AF1 function mutant mouse models in the study of mammary development. The gain of function mutant AF1_QQQ exhibits hyperactivity while the loss of function mutant AF1_FFF shows hypoactivity on mammary development. However, the involvement of AF1 is context dependent. Whereas the AF1_FFF mutation causes significant impairment in mammary development during pregnancy or in response to estrogen and progesterone, it has no effect on mammary development in nulliparous mice. Furthermore, Rankl, but not Wnt4 and Areg is a major target gene of AF1. In conclusion, PGR AF1 is a pivotal ligand-dependent activation domain critical for mammary development during pregnancy and it exerts gene specific effect on PGR regulated genes.
孕激素受体（PGR）是核受体转录因子超家族的成员。它对乳腺干细胞的扩增、乳腺导管分支和肺泡发生至关重要。PGR 的转录活性主要通过激活功能区 AF1 和 AF2 来介导。尽管 AF1 和 AF2 的发现推动了对核受体调控基因机制的理解，但它们的生理作用仍知之甚少。这主要是由于缺乏合适的遗传模型。本研究报告了在乳腺发育研究中孕激素受体 AF1 功能获得或缺失的突变体小鼠模型。功能获得性突变体 AF1_QQQ 表现出过度活跃，而功能缺失性突变体 AF1_FFF 则表现出乳腺发育的低活性。然而，AF1 的参与是依赖于背景的。虽然 AF1_FFF 突变在怀孕或对雌激素和孕激素的反应中导致乳腺发育的显著损伤，但它对未生育小鼠的乳腺发育没有影响。此外，Rankl 而不是 Wnt4 和 Areg 是 AF1 的主要靶基因。总之，PGR AF1 是一个关键的配体依赖性激活结构域，对怀孕期乳腺发育至关重要，并对 PGR 调节的基因产生特定的基因效应。
