Loss of the Max-interacting protein Mnt in mice results in decreased viability, defective embryonic growth and craniofacial defects: relevance to Miller-Dieker syndrome.

Abstract

The Mnt gene encodes a Mad-family bHLH transcription factor located on human 17p13.3. Mnt is one of 20 genes deleted in a heterozygous fashion in Miller-Dieker syndrome (MDS), a contiguous gene syndrome that consists of severe neuronal migration defects and craniofacial dysmorphic features. Mnt can inhibit Myc-dependent cell transformation and is hypothesized to counterbalance the effects of c-Myc on growth and proliferation in vivo by competing with Myc for binding to Max and by repressing target genes activated by Myc : Max heterodimers. Unlike the related Mad family members, Mnt is expressed ubiquitously and Mnt/Max heterodimers are found in proliferating cells that contain Myc/Max heterodimers, suggesting a unique role for Mnt during proliferation. To examine the role of Mnt in vivo, we produced mice with null (Mnt(KO)) and loxP-flanked conditional knock-out (Mnt(CKO)) alleles of Mnt. Virtually all Mnt(KO/KO) mutants in a mixed (129S6 x NIH Black Swiss) or inbred (129S6) genetic background died perinatally. Mnt-deficient embryos exhibited small size throughout development and showed reduced levels of c-Myc and N-Myc. In addition, 37% of the mixed background mutants displayed cleft palate as well as retardation of skull development, a phenotype not observed in the inbred mutants. These results demonstrate an important role for Mnt in embryonic development and survival, and suggest that Mnt may play a role in the craniofacial defects displayed by MDS patients.

• Authors: Kazuhito Toyo-oka, Shinji Hirotsune, Michael J Gambello, Zi-Qiang Zhou, Lorin Olson, Michael G Rosenfeld, Robert Eisenman, Peter Hurlin, Anthony Wynshaw-Boris
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 13 Issue 10 Pg. 1057-67 (May 15 2004) ISSN: 0964-6906 [Print] England
• PMID: 15028671 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Basic-Leucine Zipper Transcription Factors
• DNA-Binding Proteins
• Mnt protein, mouse
• Myc associated factor X
• Proto-Oncogene Proteins c-myc
• Repressor Proteins
• Transcription Factors
• Max protein, mouse

Topics

• Animals
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Basic-Leucine Zipper Transcription Factors
• Cleft Palate (embryology, genetics)
• Craniofacial Abnormalities (embryology, etiology, genetics)
• DNA-Binding Proteins (metabolism)
• Embryonic Development
• Fetal Growth Retardation (etiology, genetics)
• Genes, Lethal
• Mandible (abnormalities, embryology)
• Mice
• Mice, Knockout
• Occipital Bone (abnormalities, embryology)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Repressor Proteins (genetics, metabolism, physiology)
• Syndrome
• Transcription Factors (metabolism)