UMDNJ-Robert Wood Johnson Medical School, Department of Physiology and Biophysics , 683 Hoes Lane, Piscataway, NJ 08854 , USA.
Biol Open. 2012 Mar 15;1(3):182-96. doi: 10.1242/bio.2012047. Epub 2011 Dec 28.
SMRTER (SMRT-related and ecdysone receptor interacting factor) is the Drosophila homologue of the vertebrate proteins SMRT and N-CoR, and forms with them a well-conserved family of transcriptional corepressors. Molecular characterization of SMRT-family proteins in cultured cells has implicated them in a wide range of transcriptional regulatory pathways. However, little is currently known about how this conserved class of transcriptional corepressors regulates the development of particular tissues via specific pathways. In this study, through our characterization of multiple Smrter (Smr) mutant lines, mosaic analysis of a loss-of-function Smr allele, and studies of two independent Smr RNAi fly lines, we report that SMRTER is required for the development of both ovarian follicle cells and the wing. In these two tissues, SMRTER inhibits not only the ecdysone pathway, but also the Notch pathway. We differentiate SMRTER's influence on these two signaling pathways by showing that SMRTER inhibits the Notch pathway, but not the ecdysone pathway, in a spatiotemporally restricted manner. We further confirm the likely involvement of SMRTER in the Notch pathway by demonstrating a direct interaction between SMRTER and Suppressor of Hairless [Su(H)], a DNA-binding transcription factor pivotal in the Notch pathway, and the colocalization of both proteins at many chromosomal regions in salivary glands. Based on our results, we propose that SMRTER regulates the Notch pathway through its association with Su(H), and that overcoming a SMRTER-mediated transcriptional repression barrier may represent a key mechanism used by the Notch pathway to control the precise timing of events and the formation of sharp boundaries between cells in multiple tissues during development.
SMRTER（SMRT 相关和蜕皮激素受体相互作用因子）是果蝇同源物的脊椎动物蛋白 SMRT 和 N-CoR，并与它们形成了一个很好的保守家族的转录共抑制因子。在培养细胞中对 SMRT 家族蛋白的分子特征分析表明，它们参与了广泛的转录调控途径。然而，目前对于这种保守的转录共抑制因子如何通过特定途径调节特定组织的发育知之甚少。在这项研究中，通过对多个 Smrter（Smr）突变系的特征描述、功能丧失 Smr 等位基因的嵌合体分析以及两个独立的 Smr RNAi 品系的研究，我们报告 SMRTER 对于卵巢滤泡细胞和翅膀的发育都是必需的。在这两种组织中，SMRTER 不仅抑制蜕皮激素途径，还抑制 Notch 途径。我们通过显示 SMRTER 以时空限制的方式抑制 Notch 途径，而不是蜕皮激素途径，来区分 SMRTER 对这两种信号通路的影响。我们进一步通过证明 SMRTER 与 Suppressor of Hairless [Su(H)]（Notch 途径中关键的 DNA 结合转录因子）之间存在直接相互作用，以及这两种蛋白质在唾液腺中的许多染色体区域的共定位，来证实 SMRTER 可能参与 Notch 途径。基于我们的结果，我们提出 SMRTER 通过与 Su(H) 的结合来调节 Notch 途径，并且克服 SMRTER 介导的转录抑制障碍可能代表 Notch 途径用于控制事件的精确时间和在发育过程中多个组织中细胞之间形成清晰边界的关键机制。
