International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

I27. A Potential Role for Mnt in Craniofacial Defects of the Miller-Dieker Syndrome (MDS)

Kazuhito Toyo-oka1, Michael Gambello1, Shinji Hirotsune2, Peter Hurlin3 and Anthony Wynshaw-Boris1
1 Department of Pediatrics, University of California, San Diego, School of Medicine,
2 The Institute of Animal Genetics, 3 Shriners Hospital for Children

Miller-Dieker syndrome (MDS) and some cases of Isolated lissencephaly sequence (ILS) are the result of haploinsufficiency at human chromosome 17p13.3. Mutations or deletions of LIS1 gene are responsible for classical lissencephaly in some cases of ILS and MDS patients. However, the patients with MDS have larger, more-telomeric deletions detected by fluorescence in situ hybridization (FISH) than patients with ILS. This suggests that the more-severe phenotype seen in MDS patients may be due to haploinsufficiency of additional genes. Several other genes have been mapped to the MDS region. Here, we describe the phenotype of a null mutant for one of these genes, Mnt.

Mnt is a basic Helix-Loop-Helix protein that binds to Max and competes with Myc/Max complex for binding to E-box promoter sites. This usually results in suppression of transcription from E-box promoters, although in some cases Mnt/Max dimers may activate transcription. Mnt conditional mutant mice were produced using gene targeting, and these were used to produce null alleles of the Mnt gene. Almost all Mnt deficient mice are small (about 60% of wild type at weight) and die at birth. Approximately 30% of Mnt deficient mice displayed cleft palate and the expression of TGF-b was reduced in the palate region. There is a binding site for Mnt on the promoter region of the TGF-b gene, at least TGF-b2 and TGF-b2 or TGF-b3 deficient mice display cleft palate. Taken together, these results suggest that Mnt plays an important role in the expression of TGF-b, which is important for the correct development of the palate. In addition to cleft palate, there is a defect in formation of skull and palatine bone of Mnt deficient mice. The mutants display hypoplasia of the skull, interparietal bone and precursor cartilage of interparietal bone, as well as aplasia of palatine bone. These results suggest that Mnt is important for the formation of the palate as well as the skull and the development of palatine bone.

Our findings provide the first evidence that Mnt is crucial for craniofacial development. Although Mnt heterozygous deficient mice do not have any significant defects, our findings suggest that loss of function of Mnt may be involved in the development of the craniofacial defects in MDS patients

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