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 MN1 in cancer, we generated Mn1 knockout mice. Mn1 ؉/؊ animals were followed for 30 months, but they had no higher incidence of tumor formation than wild-type littermates. Mn1 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 hypoplastic membranous bones and incomplete penetrance of the cleft palate were observed. We conclude that Mn1 is an important factor in development of membranous bones.The MN1 gene, localized on human chromosome 22, was cloned by our research group in 1995 as a candidate gene for sporadic meningioma, a benign brain tumor arising from the arachnoidal cap cells found on the surface coverings (called meninges) of the brain (12). In a meningioma, the MN1 gene was found disrupted by a balanced translocation (4;22)(p16; q11). The breakpoint of the translocation lies within the first exon of the MN1 gene, and the (truncated) protein was not detected. However, no mutations or deletions of the MN1 gene were found in other meningiomas; thus the causative relationship between MN1 and meningiomas remains unclear. Subsequently, the MN1 gene was found to play a role in acute myeloid leukemia (1). The translocation (12;22)(p13;q11) creates a fusion between the MN1 and TEL (or ETV6) genes, resulting in the MN1TEL gene. The TEL protein is a member of the ETS family of transcription factors and contributes its C-terminal DNA binding domain (DBD) to the fusion protein MN1TEL. The MN1 protein donates 1,259 amino acids, 95% of its entire length, to the fusion protein. The fusion protein MN1TEL has transforming activity on NIH 3T3 cells and most likely acts as a deregulated transcription factor. MN1TEL may adhere to genes via the TEL moiety and activate these genes whereas they are normally controlled by the repressor TEL (2).The MN1 gene comprises two exons and encodes a protein of 1,319 amino acids. The amino acid sequence shows no homology to other proteins or with specific domains with known functions. However, several proline/glutamine-rich regions and a polyglutamine stretch are present and point to a function in transcription regulation. We have shown previously that MN1 activates the transcription activity of ...

The activin and TGF-beta type II receptors are members of a separate subfamily of transmembrane receptors with intrinsic protein kinase activity, which also includes the recently cloned TGF-beta type I receptor. We have isolated and characterized a cDNA clone (C14) encoding a new member of this subfamily. The domain structure of the C14-encoded protein corresponds with the structure of the other known transmembrane serine/threonine kinase receptors. It also contains the two inserts in the kinase domain that are characteristic for this subfamily. Using in situ hybridization, C14 mRNA was detected in the mesenchymal cells located adjacent to the mullerian ducts of males and females at day 15 (E15) of embryonic development. Marked C14 mRNA expression was also detected in the female gonads. In female E16 embryos, the C14 mRNA expression pattern remained similar to that in E15 embryos. However, in male E16 embryos C14 mRNA was detected in a circular area that includes the degenerating mullerian duct. The expression of C14 mRNA was also studied using RNase protection assays. At E15 and E16, C14 mRNA is expressed in the female as well as in the male urogenital ridge. However, at E19, a high C14 mRNA level in the female urogenital ridge contrasts with a lack of C14 mRNA in the male urogenital ridge. This correlates with the almost complete degeneration of the mullerian ducts in male embryos at E19. C14 mRNA expression was also detected in embryonic testes at E15, E16 and E19 using RNase protection assays, but at much lower levels than those found in the developing ovaries.(ABSTRACT TRUNCATED AT 250 WORDS)