Germline Proliferation Is Regulated by Somatic Endocytic Genes via JNK and BMP Signaling in Drosophila

• Published in: Genetics (Austin) Vol. 206; no. 1; pp. 189 - 197
• Main Authors: Tang, Yaning, Geng, Qing, Chen, Di, Zhao, Shaowei, Liu, Xian, Wang, Zhaohui
• Format: Journal Article
• Language: English
• Published: United States Genetics Society of America 01.05.2017
• Subjects: Animals; Apoptosis; Bone morphogenetic proteins; Bone Morphogenetic Proteins - genetics; Cancer; Carcinogenesis - genetics; Cdc42 protein; Cell Differentiation - genetics; Cell growth; Cell proliferation; Cell Proliferation - genetics; Cell signaling; Cellular Microenvironment - genetics; Cloning; Cysts; Developmental biology; Disease Models, Animal; Disruption; Drosophila; Drosophila melanogaster - genetics; Drosophila Proteins - biosynthesis; Drosophila Proteins - genetics; Endocytosis; Endocytosis - genetics; Female; Gene expression; Gene Expression Regulation, Developmental; Genes; Genetics; Germ cells; Germ Cells - growth & development; Homology; Humans; Insects; Investigations; Kinases; Male; MAP Kinase Kinase 4 - genetics; Mutagenesis; Neoplasms - genetics; Proteins; rab5 GTP-Binding Proteins - biosynthesis; rab5 GTP-Binding Proteins - genetics; Signal Transduction; Signaling; Somatic cells; Spermatogenesis; Stem cells; Transcription activation; Tumorigenesis; Tumors; JNK pathway; tumorigenesis; BMP/Dpp; Rab5; nonautonomous
• ISSN: 1943-2631; 0016-6731; 1943-2631
• DOI: 10.1534/genetics.116.196535

Signals derived from the microenvironment contribute greatly to tumorigenesis . The underlying mechanism requires thorough investigation. Here, we use testis 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 identified , a key factor in endocytosis, for its nonautonomous role in germline proliferation. The disruption of in 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 both transcription and germline tumor growth. Additionally, we found that multiple endocytic genes, such as , , , or , 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.