Transcriptional control of steroid biosynthesis genes in the Drosophila prothoracic gland by ventral veins lacking and knirps.
Transcriptional control of steroid biosynthesis genes in the Drosophila prothoracic gland by ventral veins lacking and knirps.
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DOI：
10.1371/journal.pgen.1004343
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发表时间：
2014-06
期刊：
影响因子：
4.5
通讯作者：
Rewitz KF
中科院分区：
文献类型：
--
作者：
Danielsen ET;Moeller ME;Dorry E;Komura-Kawa T;Fujimoto Y;Troelsen JT;Herder R;O'Connor MB;Niwa R;Rewitz KF
专门的内分泌细胞产生和释放类固醇激素，控制发育，代谢和生殖。为了合成类固醇，生物合成途径中的所有基因必须在类固醇生成细胞中协调地打开。在果蝇中，产生类固醇的内分泌细胞位于释放类固醇激素蜕皮激素的前胸腺（PG）中。蜕皮激素生物合成基因的独特PG特异性表达模式的转录调控网络仍然未知。在这里，我们表明，两个转录因子，POU结构域血管缺乏（Vvl）和核受体Knirps（Kni），在幼虫发育过程中的PG中具有重要作用。Vvl在胚胎发生期间在PG中高度表达，并且在幼虫发育期间在腺体中富集，这表明Vvl可能在该组织中作为主转录调节因子起作用。Vvl和Kni结合到表达蜕皮激素生物合成基因所需的PG特异性顺式调节元件。在PG中vvl或kni的敲低导致由于蜕皮激素产生的失败而导致幼虫发育停滞。此外，Vvl和Knl也是PG中TOR/S6 K和促前胸腺激素（PTTH）信号传导的维持所需的，这是控制蜕皮激素生物合成和PG细胞生长的两个主要途径。我们还表明，转录调节因子，蜕皮缺陷（MLD），控制早期的生物合成途径的步骤。我们的数据表明，Vvl和Kni通过生物合成基因表达的转录控制直接调节蜕皮激素的生物合成，并通过影响PTTH和TOR/S6 K信号传导间接调节蜕皮激素的生物合成。这为参与类固醇生成细胞特异性转录的协调调节的转录因子的调节网络提供了新的见解，并鉴定了Vvl和Knirps在胚胎后发育期间内分泌细胞中的新功能。类固醇激素在生理和疾病中起重要作用。这些激素是由体内内分泌细胞产生和分泌的分子，控制性成熟，新陈代谢和生殖。我们发现了转录调节因子，它是内分泌类固醇产生细胞专门功能的基础。在果蝇（Drosophila）的类固醇产生细胞中，缺乏血管（Vvl）和Knirps（Kni）打开了类固醇产生所需的所有基因。当Vvl或Kni在产生激素的细胞中失活时，参与类固醇产生的基因没有被激活。由于类固醇产生减少，幼虫无法发育并经历成熟至成年。Vvl和Kni的失活还通过干扰内分泌细胞对生长促进信号的响应来降低内分泌细胞生长。人类中具有Vvl同源物缺失的遗传变异与类固醇产生不足引起的疾病有关。连同Vvl在果蝇的类固醇产生细胞中高度表达的事实，这表明Vvl可能是类固醇产生的保守主调节因子。我们的研究结果提供了对控制内分泌细胞功能和类固醇激素水平的因素网络的深入了解，这些因素可能对人类疾病有影响。
Specialized endocrine cells produce and release steroid hormones that govern development, metabolism and reproduction. In order to synthesize steroids, all the genes in the biosynthetic pathway must be coordinately turned on in steroidogenic cells. In Drosophila, the steroid producing endocrine cells are located in the prothoracic gland (PG) that releases the steroid hormone ecdysone. The transcriptional regulatory network that specifies the unique PG specific expression pattern of the ecdysone biosynthetic genes remains unknown. Here, we show that two transcription factors, the POU-domain Ventral veins lacking (Vvl) and the nuclear receptor Knirps (Kni), have essential roles in the PG during larval development. Vvl is highly expressed in the PG during embryogenesis and is enriched in the gland during larval development, suggesting that Vvl might function as a master transcriptional regulator in this tissue. Vvl and Kni bind to PG specific cis-regulatory elements that are required for expression of the ecdysone biosynthetic genes. Knock down of either vvl or kni in the PG results in a larval developmental arrest due to failure in ecdysone production. Furthermore, Vvl and Kni are also required for maintenance of TOR/S6K and prothoracicotropic hormone (PTTH) signaling in the PG, two major pathways that control ecdysone biosynthesis and PG cell growth. We also show that the transcriptional regulator, Molting defective (Mld), controls early biosynthetic pathway steps. Our data show that Vvl and Kni directly regulate ecdysone biosynthesis by transcriptional control of biosynthetic gene expression and indirectly by affecting PTTH and TOR/S6K signaling. This provides new insight into the regulatory network of transcription factors involved in the coordinated regulation of steroidogenic cell specific transcription, and identifies a new function of Vvl and Knirps in endocrine cells during post-embryonic development. Steroid hormones play important roles in physiology and disease. These hormones are molecules produced and secreted by endocrine cells in the body and control sexual maturation, metabolism and reproduction. We found transcriptional regulators that underlie the specialized function of endocrine steroid-producing cells. In the steroid-producing cells of the fruit fly Drosophila, Ventral veins lacking (Vvl) and Knirps (Kni) turn on all the genes required for steroid production. When Vvl or Kni were inactivated in the cells where the hormone is made, the genes involved in steroid production were not activated. Because of the reduced steroid production, the juvenile larvae failed to develop and undergo maturation to adulthood. Inactivation of Vvl and Kni also reduces endocrine cell growth by disturbing their response to growth promoting signals. Genetic variations in humans with the loss of a homolog of Vvl have been associated with disorders caused by insufficient steroid production. Together with the fact that Vvl is highly expressed in the steroid-producing cells of Drosophila, this suggests that Vvl may be a conserved master regulator of steroid production. Our findings provide insight into the network of factors that control endocrine cell function and steroid hormone levels that could have implication for human diseases.
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影响因子：
16.6
作者：
Fabrowski, Piotr;Necakov, Aleksandar S.;Mumbauer, Simone;Loeser, Eva;Reversi, Alessandra;Streichan, Sebastian;Briggs, John A. G.;De Renzis, Stefano
通讯作者：
De Renzis, Stefano
影响因子：
4.5
作者：
Chrostek E;Marialva MS;Esteves SS;Weinert LA;Martinez J;Jiggins FM;Teixeira L
通讯作者：
Teixeira L
影响因子：
11.4
作者：
Arnosti, DN;Gray, S;Levine, M
通讯作者：
Levine, M
影响因子：
4.6
作者：
Gibbens, Ying Y.;Warren, James T.;O'Connor, Michael B.
通讯作者：
O'Connor, Michael B.
影响因子：
4.6
作者：
Huang, X;Suyama, K;Scott, MP
通讯作者：
Scott, MP