The RNA-binding protein DND1 acts Sequentially as a negative regulator of pluripotency and a positive regulator of epigenetic modifiers required for germ cell reprogramming.
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The adult spermatogonial stem cell population arises from pluripotent primordial germ cells (PGCs) that enter the fetal testis around embryonic day (E)10.5. PGCs undergo rapid mitotic proliferation, then enter prolonged cell cycle arrest (G1/G0) during which they transition to pro-spermatogonia. In mice homozygous for the Ter mutation in the RNA-binding protein Dnd1 (Dnd1 Ter/Ter ), many male germ cells (MGCs) fail to enter G1/G0, and form teratomas, tumors containing many embryonic cell types. To investigate the origin of these tumors, we sequenced the MGC transcriptome in Dnd1 Ter/Ter mutants at E12.5, E13.5, and E14.5, just prior to teratoma formation, and correlated this information with DO-RIP-Seq identified DND1 direct targets. Consistent with previous results, we found DND1 controls down-regulation of many genes associated with pluripotency and active cell cycle, including mTor, Hippo and Bmp/Nodal signaling pathway elements. However, DND1 targets also include genes associated with male differentiation including a large group of chromatin regulators activated in wild type but not mutant MGCs during the E13.5 and E14.5 transition. Results suggest multiple DND1 functions, and link DND1 to initiation of epigenetic modifications in MGCs.
Published Version (Please cite this version)10.1242/dev.175950
Publication InfoKeene, Jack; Capel, Blanche; Ruthig, Victor A; Friedersdorf, Matthew B; Garness, Jason A; Munger, Steve C; & Bunce, Corey (2019). The RNA-binding protein DND1 acts Sequentially as a negative regulator of pluripotency and a positive regulator of epigenetic modifiers required for germ cell reprogramming. Development (Cambridge, England). pp. dev.175950-dev.175950. 10.1242/dev.175950. Retrieved from https://hdl.handle.net/10161/19142.
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James B. Duke Professor of Cell Biology
In mammals, the primary step in male sex determination is the initiation of testis development in the bipotential gonad primordium. This step depends on the Y-linked male sex-determining gene, Sry. Expression of Sry in the XY gonad, or as a transgene in an XX gonad, leads to the differentiation of Sertoli cells. Failures in Sertoli cell differentiation in the XY gonad result in sex reversal and ovary formation. In addition to Sertoli cell differentiation, we are studying the s
James B. Duke Professor of Molecular Genetics and Microbiology
The Keene Laboratory has a long-term interest in the structure and function of viral and mammalian genomes. Having determined the first genomic sequences for rabies, Ebola, Marburg and vesicular stomatitis virus, and discerned the origins of defective interfering viruses, interests shifted to the cloning of six human genes involved in autoimmune reactivity. This resulted in the identification of numerous autoimmune RRM-type RNA-binding proteins the discovery of the RRM, and the RNA targets
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