Monahan Amanda J, Starz-Gaiano Michelle
Department of Biological Sciences, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD, 21250, USA.
Present Address: Department of Medicine, Division of Infectious Disease, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
BMC Dev Biol. 2016 Mar 18;16:5. doi: 10.1186/s12861-016-0103-3.
Microenvironments called niches maintain resident stem cell populations by balancing self-renewal with differentiation, but the genetic regulation of this process is unclear. The niche of the Drosophila testis is well-characterized and genetically tractable, making it ideal for investigating the molecular regulation of stem cell biology. The JAK/STAT pathway, activated by signals from a niche component called the hub, maintains both germline and somatic stem cells.
This study investigated the molecular regulation of the JAK/STAT pathway in the stem cells of the Drosophila testis. We determined that the transcriptional regulator Apontic (Apt) acts in the somatic (cyst) stem cells (CySCs) to balance differentiation and maintenance. We found Apt functions as a negative feedback inhibitor of STAT activity, which enables cyst cell maturation. Simultaneous loss of the STAT regulators apt and Socs36E, or the Stat92E-targeting microRNA miR-279, expanded the somatic stem cell-like population.
Genetic analysis revealed that a conserved genetic regulatory network limits JAK/STAT activity in the somatic stem cells of Drosophila testis. In these cells, we determined JAK/STAT signaling promotes apt expression. Then, Apt functions through Socs36E and miR-279 to attenuate pathway activation, which is required for timely CySC differentiation. We propose that Apt acts as a core component of a STAT-regulatory circuit to prevent stem cell overpopulation and allow stem cell maturation.
被称为生态位的微环境通过平衡自我更新与分化来维持常驻干细胞群体，但这一过程的基因调控尚不清楚。果蝇睾丸的生态位特征明确且易于进行基因操作，使其成为研究干细胞生物学分子调控的理想模型。由名为枢纽的生态位成分发出的信号激活的JAK/STAT信号通路维持着生殖系干细胞和体细胞干细胞。
本研究调查了果蝇睾丸干细胞中JAK/STAT信号通路的分子调控机制。我们确定转录调节因子Apontic（Apt）在体细胞（包囊）干细胞（CySCs）中发挥作用，以平衡分化和维持。我们发现Apt作为STAT活性的负反馈抑制剂，促进包囊细胞成熟。同时缺失STAT调节因子apt和Socs36E，或靶向Stat92E的微小RNA miR-279，会扩大体细胞干细胞样群体。
遗传分析表明，一个保守的基因调控网络限制了果蝇睾丸体细胞干细胞中的JAK/STAT活性。在这些细胞中，我们确定JAK/STAT信号传导促进apt表达。然后，Apt通过Socs36E和miR-279发挥作用，减弱信号通路激活，这是CySC及时分化所必需的。我们提出Apt作为STAT调节回路的核心成分，可防止干细胞过度增殖并促进干细胞成熟。
