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

Toyo-oka, Kazuhito and Hirotsune, Shinji and Gambello, Michael J and Zhou, Zi-Qiang and Olson, Lorin and Rosenfeld, Michael G and Eisenman, Robert and Hurlin, Peter and Wynshaw-Boris, Anthony (2004) Loss of the Max-interacting protein Mnt in mice results in decreased viability, defective embryonic growth and craniofacial defects: relevance to Miller-Dieker syndrome. Human molecular genetics, 13 (10). pp. 1057-1067. ISSN 0964-6906

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Article URL: http://hmg.oxfordjournals.org/cgi/content/full/13/...

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.

Item Type: Article
Additional Information: The final published version of this article is available at the journal website.
DOI: 10.1093/hmg/ddh116
PubMed ID: 15028671
Grant Numbers: NS39404, CA87788, CA20525, DK18477
Keywords or MeSH Headings: 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;
Subjects: Molecules > Proteins > Transcription factors
Molecules > Genes
Cellular and Organismal Processes > Development
Depositing User: Library Staff
Date Deposited: 21 Nov 2008 23:37
Last Modified: 13 May 2010 21:00
URI: http://authors.fhcrc.org/id/eprint/190

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