Regulation of male germ cell cycle arrest and differentiation by DND1 is modulated by genetic background

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2011

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Abstract

Human germ cell tumors show a strong sensitivity to genetic background similar to Dnd1(Ter/Ter) mutant mice, where testicular teratomas arise only on the 129/SvJ genetic background. The introduction of the Bax mutation onto mixed background Dnd1(Ter/Ter) mutants, where teratomas do not typically develop, resulted in a high incidence of teratomas. However, when Dnd1(Ter/Ter); Bax(-/-) double mutants were backcrossed to C57BL/6J, no tumors arose. Dnd1(Ter/Ter) germ cells show a strong downregulation of male differentiation genes including Nanos2. In susceptible strains, where teratomas initiate around E15.5-E17.5, many mutant germ cells fail to enter mitotic arrest in G0 and do not downregulate the pluripotency markers NANOG, SOX2 and OCT4. We show that DND1 directly binds a group of transcripts that encode negative regulators of the cell cycle, including p27(Kip1) and p21(Cip1). P27(Kip1) and P21(Cip1) protein are both significantly decreased in Dnd1(Ter/Ter) germ cells on all strain backgrounds tested, strongly suggesting that DND1 regulates mitotic arrest in male germ cells through translational regulation of cell cycle genes. Nonetheless, in C57BL/6J mutants, germ cells arrest prior to M-phase of the cell cycle and downregulate NANOG, SOX2 and OCT4. Consistent with their ability to rescue cell cycle arrest, C57BL/6J germ cells overexpress negative regulators of the cell cycle relative to 129/SvJ. This work suggests that reprogramming of pluripotency in germ cells and prevention of tumor formation requires cell cycle arrest, and that differences in the balance of cell cycle regulators between 129/SvJ and C57BL/6 might underlie differences in tumor susceptibility.

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Cook,Matthew S.;Munger,Steven C.;Nadeau,Joseph H.;Capel,Blanche. 2011. Regulation of male germ cell cycle arrest and differentiation by DND1 is modulated by genetic background. Development 138(1): 23-32.

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10.1242/dev.057000

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Capel

Blanche Capel

James B. Duke Distinguished 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. 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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