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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2019-06-28
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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.
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Ruthig, Victor A, Matthew B Friedersdorf, Jason A Garness, Steve C Munger, Corey Bunce, Jack D Keene and Blanche Capel (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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Scholars@Duke
Blanche Capel
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. We are also interested in the biology of germ cells -- the cells that give rise to eggs and sperm. I have had a longstanding interest in the communication between Sertoli cells and germ cells in fetal life and afterwards, once the seminiferous epithelium is established. In adult life, each Sertoli cell communicates with germ cells at multiple stages of development from spermatogonial stem cells located at their base to elongated spermatids, released at their apical surface. How can Sertoli cells direct specific information to each of the germ cells wedged between their cell membranes? This problem previously seemed unapproachable, because it was so difficult to figure out where to anchor the analysis, and the cost of transgenics seemed prohibitive. However, recently we have been collaborating with a colleague in my department (Scott Soderling) who has designed an AAV system to deliver CRISPR and tag genetic loci in vivo with BioID for proximity protein labeling. We found that we can deliver the backbone AAV to Sertoli cell within seminiferous tubules with high efficiency by injection into the rete testis. Combining expertise of our labs provides an opportunity to do a similar analysis in Sertoli cells with the goal of identifying localized communication between Sertoli cells and the germ cells they support.
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