Subject(s)
Melanoma , Skin Neoplasms , Veterans , Humans , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Ipilimumab/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Mitogen-Activated Protein Kinase Kinases , Antineoplastic Combined Chemotherapy ProtocolsABSTRACT
Active adult stem cells maintain a bipotential state with progeny able to either self-renew or initiate differentiation depending on extrinsic signals from the surrounding microenvironment. However, the intrinsic gene regulatory networks and chromatin states that allow adult stem cells to make these cell fate choices are not entirely understood. Here we show that the transcription factor DNA Replication-related Element Factor (DREF) regulates adult stem cell maintenance in the Drosophila male germline. A temperature-sensitive allele of DREF described in this study genetically separated a role for DREF in germline stem cell self-renewal from the general roles of DREF in cell proliferation. The DREF temperature-sensitive allele caused defects in germline stem cell self-renewal but allowed viability and division of germline stem cells as well as cell viability, growth and division of somatic cyst stem cells in the testes and cells in the Drosophila eye. Germline stem cells mutant for the temperature sensitive DREF allele exhibited lower activation of a TGF-beta reporter, and their progeny turned on expression of the differentiation factor Bam prematurely. Results of genetic interaction analyses revealed that Mi-2 and Caf1/p55, components of the Nucleosome Remodeling and Deacetylase (NuRD) complex, genetically antagonize the role of DREF in germline stem cell maintenance. Taken together, these data suggest that DREF contributes to intrinsic components of the germline stem cell regulatory network that maintains competence to self-renew.
Subject(s)
Adenosine Triphosphatases/genetics , Adult Stem Cells/metabolism , Autoantigens/genetics , Drosophila Proteins/genetics , Retinoblastoma-Binding Protein 4/genetics , Transcription Factors/genetics , Animals , Cell Differentiation/genetics , Cell Proliferation/genetics , Cell Self Renewal/genetics , Drosophila melanogaster/genetics , Drosophila melanogaster/growth & development , Germ Cells/growth & development , Male , Mi-2 Nucleosome Remodeling and Deacetylase Complex/genetics , Stem Cell Niche/genetics , Testis/growth & development , Testis/metabolism , Transforming Growth Factor beta/geneticsABSTRACT
Specialized microenvironments, or niches, provide signaling cues that regulate stem cell behavior. In the Drosophila testis, the JAK-STAT signaling pathway regulates germline stem cell (GSC) attachment to the apical hub and somatic cyst stem cell (CySC) identity. Here, we demonstrate that chickadee, the Drosophila gene that encodes profilin, is required cell autonomously to maintain GSCs, possibly facilitating localization or maintenance of E-cadherin to the GSC-hub cell interface. Germline specific overexpression of Adenomatous Polyposis Coli 2 (APC2) rescued GSC loss in chic hypomorphs, suggesting an additive role of APC2 and F-actin in maintaining the adherens junctions that anchor GSCs to the niche. In addition, loss of chic function in the soma resulted in failure of somatic cyst cells to maintain germ cell enclosure and overproliferation of transit-amplifying spermatogonia.
