The distal region of mouse chromosome 12 harbors the
Dlk1–Dio3 domain, is essential for normal development and encodes maternally expressed noncoding RNAs (ncRNAs), including
Gtl2 as well as paternally expressed proteins
.Gtl2 works as a tumor suppressor in several types of human cancer cell lines; however, whether this reflects its function
in vivo is unknown. Deleting
Gtl2 from the maternal allele (
Gtl2(–/+)) results in loss of expression of
Gtl2 and decreased expression of downstream ncRNAs, including many miRNAs. To determine the role of ncRNAs in tumorigenesis, we induced teratomas by engrafting E6.5 embryos (wildtype or
Gtl2(–/+)) under the kidney capsule of scid mice. Some teratomas derived from the
Gtl2(–/+) embryos exhibited hypertrophic growth, suggesting that ncRNAs, including
Gtl2, may act as tumor suppressors
in vivo. Microarray analysis of miRNAs expressed by
Gtl2(–/+) teratomas revealed decreased expression of 28 miRNAs encoded by the
Dlk1–Dio3 domain, low expression of embryonic stem cell-specific miRNAs and dysregulation of miRNAs involved in tumorigenesis. This study suggests that downregulation of ncRNAs in the
Dlk1-Dio3 domain leads to enhanced teratoma growth and repression of stem cell markers.
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