Germline Proliferation Is Regulated by Somatic Endocytic Genes via JNK and BMP Signaling inDrosophila.
Signals derived from the microenvironment contribute greatly to tumorigenesis . The underlying mechanism requires thorough investigation. Here, we useDrosophilatestis as a model system to address this question, taking the advantage of the ease to distinguish germline and somatic cells and to track the cell numbers. In an EMS mutagenesis screen, we identifiedRab5, a key factor in endocytosis, for its nonautonomous role in germline proliferation. The disruption ofRab5in somatic cyst cells, which escort the development of germline lineage, induced the overproliferation of underdifferentiated but genetically wild-type germ cells. We demonstrated that this nonautonomous effect was mediated by the transcriptional activation of Dpp [the fly homolog of bone morphogenetic protein (BMP)] by examining the Dpp-reporter expression and knocking down Dpp to block germline overgrowth. Consistently, the protein levels of Bam, the germline prodifferentiation factor normally accumulated in the absence of BMP/Dpp signaling, decreased in the overproliferating germ cells. Further, we discovered that the JNK signaling pathway operated between Rab5 and Dpp, because simultaneously inhibiting the JNK pathway and Rab5 in cyst cells prevented bothdpptranscription and germline tumor growth. Additionally, we found that multiple endocytic genes, such asavl,TSG101,Vps25, orCdc42, were required in the somatic cyst cells to restrict germline amplification. These findings indicate that when the endocytic state of the surrounding cells is impaired, genetically wild-type germ cells overgrow. This nonautonomous model of tumorigenesis provides a simple system to dissect the relation between tumor and its niche.
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Chaoyang, Beijing, China 100101.|University of Chinese Academy of Sciences, Huairou, Beijing, China 101408.
Yaning
Y
Tang
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Chaoyang, Beijing, China 100101 zhwang@genetics.ac.cn qgeng@genetics.ac.cn.
Qing
Q
Geng
University of Chinese Academy of Sciences, Huairou, Beijing, China 101408.
Di
D
Chen
University of Chinese Academy of Sciences, Huairou, Beijing, China 101408.
Shaowei
S
Zhao
University of Chinese Academy of Sciences, Huairou, Beijing, China 101408.
Xian
X
Liu
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Chaoyang, Beijing, China 100101 zhwang@genetics.ac.cn qgeng@genetics.ac.cn.
Zhaohui
Z
Wang
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D060833:Cellular Microenvironment / Q000235:genetics; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics; D004705:Endocytosis / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000254:growth & development; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics*; D008297:Male; D009369:Neoplasms / Q000235:genetics; D015398:Signal Transduction; D020696:rab5 GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*
D019485:Bone Morphogenetic Proteins; D029721:Drosophila Proteins; C064196:dpp protein, Drosophila; D048670:MAP Kinase Kinase 4; C586289:Rab5 protein, Drosophila; D020696:rab5 GTP-Binding Proteins
BMP/Dpp; JNK pathway; Rab5; nonautonomous; tumorigenesis