Institut de recherches cliniques de Montréal, Laboratoire de génétique moléculaire, Montréal, Québec, Canada.
J Neuroendocrinol. 2022 Aug;34(8):e13147. doi: 10.1111/jne.13147. Epub 2022 May 7.
During development, highly specialized differentiated cells, such as pituitary secretory cells, acquire their identity and properties through a series of specification events exerted by transcription factors to implement a unique gene expression program and epigenomic state. The investigation of these developmental processes informs us on the unique features of a cell lineage, both to explain these features and also to outline where these processes may fail and cause disease. This review summarizes present knowledge on the developmental origin of pituitary corticotroph and melanotroph cells and on the underlying molecular mechanisms. At the onset, comparison of gene expression programs active in pituitary progenitors compared to those active in differentiated corticotrophs or melanotrophs indicated dramatic differences in the control of, for example, the cell cycle. Tpit is the transcription factor that determines terminal differentiation of pro-opiomelanocortin (POMC) lineages, both corticotrophs and melanotrophs, and its action involves this switch in cell cycle control in parallel with activation of cell-specific gene expression. There is thus far more to making a corticotroph cell than just activating transcription of the POMC gene. Indeed, Tpit also controls implementation of mechanisms for enhanced protein translation capacity and development of extensive secretory organelles. The corticotroph cell identity also includes mechanisms responsible for homotypic cell-cell interactions between corticotrophs and for privileged heterotypic cell interactions with pituitary cells of other lineages. The review also summarizes current knowledge on how a pioneer transcription factor, Pax7, remodels the epigenome such that the same determination transcription factor, Tpit, will implement the melanotroph program of gene expression. Finally, this canvas of regulatory mechanisms implementing POMC lineage identities constitutes the background to understand alterations that characterize corticotroph adenomas of Cushing's disease patients. The integration of all these data into a unified scheme will likely yield a scheme to globally understand pathogenic mechanisms in Cushing's disease.
在发育过程中，高度特化的分化细胞，如垂体分泌细胞，通过转录因子施加的一系列特化事件获得其身份和特性，以实现独特的基因表达程序和表观基因组状态。对这些发育过程的研究使我们了解了细胞谱系的独特特征，不仅可以解释这些特征，还可以概述这些过程可能失败并导致疾病的地方。 这篇综述总结了目前关于垂体促肾上腺皮质细胞和黑素细胞的发育起源以及潜在分子机制的知识。 首先，比较垂体祖细胞中活跃的基因表达程序与分化的促肾上腺皮质细胞或黑素细胞中活跃的基因表达程序表明，细胞周期的控制存在显著差异，例如，Tpit 是决定前阿黑皮素原 (POMC) 谱系终末分化的转录因子，包括促肾上腺皮质细胞和黑素细胞，其作用涉及细胞周期控制的这种转变，同时激活细胞特异性基因表达。 制造促肾上腺皮质细胞不仅仅是激活 POMC 基因的转录。 事实上，Tpit 还控制增强蛋白质翻译能力的机制的实施和广泛分泌细胞器的发育。 促肾上腺皮质细胞的身份还包括负责促肾上腺皮质细胞之间同质细胞-细胞相互作用以及与其他谱系的垂体细胞的特权异质细胞相互作用的机制。 该综述还总结了目前关于先驱转录因子 Pax7 如何重塑表观基因组的知识，以便相同的决定转录因子 Tpit 将实施黑素细胞的基因表达程序。 最后，实施 POMC 谱系身份的调节机制的这一画布构成了理解特征为库欣病患者促肾上腺皮质腺瘤的改变的背景。 将所有这些数据整合到一个统一的方案中，可能会产生一种方案来全面理解库欣病的发病机制。
