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

Abstract

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 ...

Chromosome 22q12.1 microdeletions: confirmation of the MN1 gene as a candidate gene for cleft palate

“…Heterozygous Mn1 ± mice present an intermediate phenotype, including hypoplasia of the maxillary and palatal shelves and cleft secondary palate with incomplete penetrance. 19 The role for MN1 in cleft palate development is further supported by the finding of an increased allele frequency (although not significant) at SNP rs5752638 of MN1 in patients with submucous cleft palate compared to control Figure 2 Overview of 22q12 deletions in our patient cohort, complemented with four previously reported cases 9,11,12 and one Decipher patient (Decipher 4110) with a complex chromosomal rearrangement on chromosome 22, including a de novo 2 Mb deletion of 22q12.2 and a typical duplication of the diGeorge region on 22q11. Deletions associated with overt cleft palate are depicted in deep purple, those associated with minor palatal defects (high arched palate or velopharyngeal insufficiency) in light purple, and those without palatal malformations in white.…”

MN1 overexpression is an important step in the development of inv(16) AML

“…Why MN1 overexpression would specifically affect the proliferation of GMP-derived but not MEP-derived cells is currently unknown. Mn1 knockout mice have defects in the development of membranous bones of the cranial skeleton, 40 but whether these mice also harbor hematopoietic defects is a question we are currently addressing.…”

Regional DNA methylation differences between humans and chimpanzees are associated with genetic changes, transcriptional divergence and disease genes

“…49 Furthermore, mouse Mn1 has been shown to be important for the development of membranous bones of the cranial skeleton. 50 It is conceivable that MN1 has a role in the structural difference of the cranium between humans and chimpanzees. 51 The other gene APP showed a difference in splicing pattern that was correlated with the methylation status of the exonic S-DMR.…”