Regulation of male germ cell cycle arrest and differentiation by DND1 is modulated by genetic background
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.
Type
Other articleSubject
germ cellcell cycle
testicular teratoma
mouse
congenital testicular teratomas
embryonic stem-cells
ter mutation
dead-end
suppresses meiosis
129/sv-ter mice
messenger-rna
united-states
expression
developmental biology
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https://hdl.handle.net/10161/4179Published Version (Please cite this version)
10.1242/dev.057000Citation
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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Show full item recordScholars@Duke
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. In
addition to Sertoli cell differentiation, we are studying the s

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