title: 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.affiliation: Department of Pediatrics, UCSD Cancer Center, University of California, San Diego School of Medicine, La Jolla 92093-0627, USA.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Toyo-oka
authors.forename: Shinji
authors.initials: S
authors.lastname: Hirotsune
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gambello
authors.forename: Zi-Qiang
authors.initials: ZQ
authors.lastname: Zhou
authors.forename: Lorin
authors.initials: L
authors.lastname: Olson
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.forename: Robert
authors.initials: R
authors.lastname: Eisenman
authors.forename: Peter
authors.initials: P
authors.lastname: Hurlin
authors.forename: Anthony
authors.initials: A
authors.lastname: Wynshaw-Boris
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D002972:Cleft Palate / Q000196:embryology / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000196:embryology / Q000209:etiology* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D047108:Embryonic Development; D005317:Fetal Growth Retardation / Q000209:etiology* / Q000235:genetics; D005804:Genes, Lethal; D008334:Mandible / Q000002:abnormalities / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D009777:Occipital Bone / Q000002:abnormalities / Q000196:embryology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D013577:Syndrome; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C484561:Mnt protein, mouse; C067850:Myc associated factor X; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D014157:Transcription Factors; C068422:Max protein, mouse