Targeted Disruption of the Mn1 Oncogene Results in Severe Defects in Development of Membranous Bones of the Cranial Skeleton.

Meester-Smoor, Magda A.; Vermeij, Marcel; van Helmond, Marjolein J. L.; Molijn, Anco C.; van Wely, Karel H. M.; Hekman, Arnold C. P.; Vermey-Keers, Christl; Riegman, Peter H. J.; Zwarthoff, Ellen C.

Fusion of the MN1) gene to TEL (ETV6) results in myeloid leukemia. The fusion protein combines the transcription activating domain of MN1 and the DNA binding domain of TEL and is thought to act as a deranged transcription factor. In addition, disruption of the large first exon of the MN1 gene is thought to inactivate MN1 function in a meningioma. To further investigate the role of MNJ in cancer, we generated Mnl knockout mice. Mn1 /-animals were followed for 30 months, but they had no higher incidence of tumor formation than wild-type littermates. Mnl null mice, however, were found to die at birth or shortly thereafter as the result of a cleft palate. Investigation of newborn or embryonic day 15.5 (E15.5) to E17.5 null mice revealed that the development of several bones in the skull was abnormal. The affected bones are almost exclusively formed by intramembranous ossification. They are either completely agenic at birth (alisphenoid and squamosal bones and vomer), hypoplastic, deformed (basisphenoid, pterygoid, and presphenoid), or substantially thinner (frontal, parietal, and interparietal bones). In heterozygous mice hypoptastic membranous bones and incomplete penetrance of the cleft palate were observed. We conclude that Mnl is an important factor in development of membranous bones.

ONCOGENES; OSSIFICATION; BONES; CLEFT palate; MYELOID leukemia; MOLECULAR genetics

Molecular & Cellular Biology, 2005, Vol 25, Issue 10, p4229

0270-7306

Academic Journal

10.1128/MCB.25.10.4229-4236.2005