Deletion of Mecom in mouse results in early-onset spinal deformity and osteopenia

Abstract

Recent studies have indicated a role for a MECOM allele in susceptibility to osteoporotic fractures in humans. We have generated a mutation in Mecom in mouse (termed MEm1) via lacZ knock-in into the upstream transcription start site for the gene, resulting in disruption of Mds1 and Mds1-Evi1 transcripts, but not of Evi1 transcripts. We demonstrate that MEm1/m1 mice have severe kyphoscoliosis that is reminiscent of human congenital or primary kyphoscoliosis. MEm1/m1 mice appear normal at birth, but by 2 weeks, they exhibit a slight lumbar lordosis and narrowed intervertebral space. This progresses to severe lordosis with disc collapse and synostosis, together with kyphoscoliosis. Bone formation and strength testing show that MEm1/m1 mice have normal bone formation and composition but are osteopenic. While endochondral bone development is normal, it is markedly dysplastic in its organization. Electron micrographs of the 1week postnatal intervertebral discs reveals marked disarray of collagen fibers, consistent with an inherent weakness in the non-osseous connective tissue associated with the spine. These findings indicate that lack of ME leads to a complex defect in both osseous and non-osseous musculoskeletal tissues, including a marked vertebral osteopenia, degeneration of the IVD, and disarray of connective tissues, which is likely due to an inherent inability to establish and/or maintain components of these tissues.

Clinical and genetic risk factors for decreased bone mineral density in Japanese patients with inflammatory bowel disease

“…The MECOM gene, also known as EVI , encodes a transcriptional regulator that may be involved in hematopoiesis, apoptosis, development, differentiation, and proliferation . MECOM was reported to be related to osteoporosis fractures in GWAS and Mecom‐knockout mice, which showed early‐onset spinal deformity and osteopenia . Interestingly, the loci previously shown to be associated with bone loss in the general population did not show a significant association in our IBD cohort (Table S3).…”

Exceptionally long 5′ UTR short tandem repeats specifically linked to primates

“…Remarkably, deletion of MECOM in mouse results in early-onset spinal deformity (Juneja et al, 2014). Beyond a certain length, STRs become the binding site for transcription factors (TFs).…”

Development, functional organization, and evolution of vertebrate axial motor circuits

“…Loss and gain of function studies have shown that Runx3 is required for the ability of pSNs to establish connections with MNs and other neural classes [ 77 – 79 ], suggesting that the Runx3 mutant phenotype is due to the disruption of local sensory-motor spinal reflex circuits. In addition, mutations that affect the function of the MMC-restricted transcription factor Mecom also causes abnormal bending of the spine [ 80 ], raising the possibility that this phenotype is also consequence of altered connectivity between axial MNs and premotor neural populations.…”