Genetic ablation of the tumor suppressor menin causes lethality at mid-gestation with defects in multiple organs

Abstract

Patients suffering from multiple endocrine neoplasia type 1 (MEN1) are predisposed to multiple endocrine tumors. The MEN1 gene product, menin, is expressed in many embryonic, as well as adult tissues, and interacts with several proteins in vitro and in vivo. However, the biological function of menin remains largely unknown. Here we show that disruption of the Men1 gene in mice causes embryonic lethality at E11.5-E13.5. The Men1 null mutant embryos appeared smaller in size, frequently with body haemorrhages and oedemas, and a substantial proportion of them showed disclosure of the neural tube. Histological analysis revealed an abnormal development of the nervous system and heart hypotrophy in some Men1 null embryos. Furthermore, Men1 null livers generally displayed an altered organization of the epithelial and hematopoietic compartments associated with enhanced apoptosis. Chimerism analysis of embryos generated by injection of Men1 null ES cells, showed that cells lacking menin do not seem to have a general cell-autonomous defect. However, primary Men1 null embryonic fibroblasts entered senescence earlier than their wild-type counterparts. Despite normal proliferation ability, Men1 null ES cells exhibited a deficiency to form embryoid bodies, suggesting an impaired differentiation capacity in these cells. The present study demonstrates that menin plays an important role in the embryonic development of multiple organs in addition to its proposed role in tumor suppression.

Menin Is Required for Optimal Processing of the MicroRNA let-7a

“…2 is an inherited syndrome, with development of neoplasia in several endocrine organs including pancreatic islets (1)(2)(3)(4). The gene mutated in this syndrome, MEN1, encodes a nuclear protein of 610 amino acids, menin (5,6).…”

The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression

“…Since homozygous Men1 deletion in mice leads to early embryonic lethality ϳday 11 because of unknown causes (28,29), it is difficult to assess the role of menin in hematopoiesis. Although mice harboring conditional Men1 alleles (floxed Men1) and tissue-specific Cre were successfully used to determine the role of menin in tumor suppression in endocrine and liver cells (30)(31)(32)(33), these models were unable to address menin function in hematopoiesis.…”

Phosphorylation of the Menin Tumor Suppressor Protein on Serine 543 and Serine 583

“…Mouse genetic experiments, combined with human genetic data, support the conclusion that MEN1 is a tumor-suppressor gene. Heterozygous MEN1 knockout mice develop multiple endocrine tumors similar to those found in human MEN-1 patients, whereas homozygous deletion is embryonic lethal (11)(12)(13). Furthermore, disruption of the MEN1 gene in pancreatic islet h cells has been shown to result in tumor development (14,15).…”