Characterization of the mouse Men1 gene and its expression during development

Abstract

The gene responsible for multiple endocrine neoplasia type 1 (MEN1), a heritable predisposition to endocrine tumours in man, has recently been identi®ed. Here we have characterized the murine homologue with regard to cDNA sequence, genomic structure, expression pattern and chromosomal localisation. The murine Men1 gene spans approximately 6.7 kb of genomic DNA and is comprised of 10 exons with similar genomic structure to the human locus. It was mapped to the pericentromeric region of mouse chromosome 19, which is conserved with the human 11q13 band where MEN1 is located. The predicted protein is 611 amino acids in length and overall is 97% homologous to the human orthologue. The 45 reported MEN1 mutations which alter or delete a single amino acid in human all occur at conserved residues, thereby supporting their functional signi®cance. Two transcripts of approximately 3.2 and 2.8 kb were detected in both embryonal and adult murine tissues, resulting from alternative splicing of intron 1. By RNA in situ hybridization and Northern analysis the spatiotemporal expression pattern of Men1 was determined during mouse development. Men1 gene activity was detected already at gestational day 7. At embryonic day 14 expression was generally high throughout the embryo, while at day 17 the thymus, skeletal muscle, and CNS showed the strongest signal. In selected tissues from postnatal mouse Men1 was detected in all tissues analysed and was expressed at high levels in cerebral cortex, hippocampus, testis, and thymus. In brain the menin protein was detected mainly in nerve cell nuclei, whereas in testis it appeared perinuclear in spermatogonia. These results show that Men1 expression is not con®ned to organs a ected in MEN1, suggesting that Men1 has a signi®cant function in many di erent cell types including the CNS and testis.

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

“…We also examined three mutations, L22M, L22V and L22P, which have not been reported to be associated with diseases but could be generated by single nucleotide alterations from the wild-type MEN1 gene, and mouse menin, which has 20 amino acid substitutions and one amino-acid insertion with respect to human menin. (33) The normal polymorphisms exhibited almost the same expression levels as wild-type menin, while mutants associated with ASPT, FIHP or typical MEN1 showed variable expression levels in each group (Fig. 3B).…”

Reduction of Menin Expression Enhances Cell Proliferation and Is Tumorigenic in Intestinal Epithelial Cells

“…Menin is highly conserved in humans and rodents (5,6). The protein sequence does not include consensus motives from which its putative function could be deduced.…”

Proliferation-Associated Expression of the MEN1 Gene as Revealed by In Situ Hybridization: Possible Role of the Menin as a Negative Regulator of Cell Proliferation Under DNA Damage

“…Menin has been demonstrated to be a nuclear protein (Guru et al, 1998) which functionally interacts with the AP1 transcription factor JunD (Agarwal et al, 1999;Gobl et al, 1999). The wide expression of the Men1 transcript in early stage of mouse embryogenesis suggests that this gene may play a role in fetal development (Bassett et al, 1999;Stewart et al, 1998). In humans, the ubiquitous expression of the MEN1 gene in endocrine and non-endocrine organs, as examined by northern blotting, has been reported (The European Consortium on MEN1, 1997), but the detailed cellular distribution of the MEN1 transcript in each tissue has not been examined in any species.…”