Disease relevance of Msx1

• The Msx1 gene controls many aspects of craniofacial development, as evidenced by craniofacial abnormalities seen in Msx1(-/-) mice, including the arrest of tooth development and the absence of the alveolar bone [1].
• Homozygous mutant mice die at birth with facial defects (see Satokata, I. and Maas, R. (1994) Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat. Genet. 6, 348-356) [2].
• These data establish that Lmx1a and Msx1 are critical intrinsic dopamine-neuron determinants in vivo and suggest that they may be essential tools in cell replacement strategies in Parkinson's disease [3].

High impact information on Msx1

• Here we show that the homeodomain proteins Lmx1a and Msx1 function as determinants of midbrain dopamine neurons, cells that degenerate in patients with Parkinson's disease [3].
• Most Msx2-mutant phenotypes, including calvarial defects, are enhanced by genetic combination with Msx1 loss of function, indicating that Msx gene dosage can modify expression of the PFM phenotype [4].
• Forced expression of Msx1 represses myoD enhancer activity [5].
• MSX1 is expressed in primary human fibroblasts and in 10T1/2 cells containing human chromosome 4, while parental 10T1/2 cells do not express Msx1 [5].
• The Msx1 homeobox gene is expressed at diverse sites of epithelial-mesenchymal interaction during vertebrate embryogenesis, and has been implicated in signalling processes between tissue layers [6].

Chemical compound and disease context of Msx1

• These data suggest a mechanistic interaction between retinoic acid, transforming growth factor beta, and Msx-1 in the etiology of retinoic acid-induced cleft palate [7].

Biological context of Msx1

• Moreover, in contrast to the tooth bud stage arrest observed in Msx1 mutants, Msx1,Msx2 double mutants exhibit an earlier phenotype closely resembling the lamina stage arrest observed in Dlx1,Dlx2 double mutants [8].
• Msx1 expression was investigated in the context of the onset of dermis formation monitored by the Dermo1 gene expression [9].
• Msx1 controls inductive signaling in mammalian tooth morphogenesis [10].
• In the underlying mesenchyme of AER-free areas, cell proliferation was reduced, and transcription of Shh and Msx1 was diminished [11].
• Taking advantage of an nlacZ reporter gene integrated into the mouse Msx1 locus (Msx1(nlacZ) allele), we detected segmental expression of the Msx1 gene in cells of the dorsal mesenchyme of the trunk between embryonic days 11 and 14 [9].

Anatomical context of Msx1

• Early expression of Islet1 in presumptive incisor epithelium is coincident with expression of Bmp4, which acts to induce Msx1 expression in the underlying mesenchyme [12].
• Cells expressing the Msx1 gene would migrate from the somite and contribute to the dermis of the dorsalmost trunk region [9].
• To further analyze the role of Msx1 in regulating epithelial-mesenchymal interactions during tooth morphogenesis, we have examined the expression of several potential Msx1 downstream genes in Msx1 mutant tooth germs and we have performed functional experiments designed to order these genes into a pathway [10].
• The expression of the homeobox gene Msx1 reveals two populations of dermal progenitor cells originating from the somites [9].
• The gene is downregulated prior to the onset of dermis differentiation, suggesting a role for Msx1 in the control of this process [9].

Associations of Msx1 with chemical compounds

• Regardless of cholesterol content, high fat diets induced mineralization of the proximal aorta (assessed by von Kossa staining) and promoted aortic expression of Msx2 and Msx1, genes encoding homeodomain transcription factors that regulate mineralization and osseous differentiation programs in the developing skull [13].
• The gradients of Msx1 and Neuropilin-2 expression in basal cells and neurons, respectively, correlated with expression of a retinoic acid-synthesizing enzyme (RALDH2) in lamina propria [14].
• Histologic sections showed that progenitor as well as differentiating and differentiated cells of all the bone cell lineages could express the Msx1 protein (chondrocytes, osteoblasts, tartrate-resistant acid phosphatase positive osteoclasts and chondroclasts) [15].
• Utilizing a series of truncated Msx-1 polypeptides, we show that multiple regions of Msx-1 contribute to repression, and these are rich in alanine, glycine, and proline residues [16].
• Importantly, a perfect reverse complement of (C/G)TTAATTG, which was recently shown to be an optimal binding sequence for the homeodomain of Msx-1 protein (K.M. Catron, N. Iler, and C. Abate (1993) Mol. Cell. Biol. 13:2354-2365), was also located in the murine Msx-1 promoter [17].

Physical interactions of Msx1

• SMAD 8 binding to mice Msx1 basal promoter is required for transcriptional activation [18].

Co-localisations of Msx1

• In addition, Id colocalizes both spatially and temporally with Hox-7.1, a murine homeobox gene which is associated with regions of high cell proliferation and positional fate assignment [19].

Regulatory relationships of Msx1

• FGFs and BMP4 induce both Msx1-independent and Msx1-dependent signaling pathways in early tooth development [8].
• The Msx1 gene in mice has been proven to be induced by BMP (bone morphogenetic protein) proteins, and three binding sites for SMAD, an intracellular BMP signalling transducer, have already been identified in its promoter [18].
• Furthermore, electroporation in the chick embryo demonstrates that Msx1 can induce Wnt1 expression in the diencephalon neuroepithelium and in the lateral ectoderm [20].
• We report here that Msx1 (formerly Hox-7.1) is expressed at high levels in uterine epithelial cells of the non-pregnant adult [21].
• In the embryonic CNS, the Msx1 gene is expressed along the dorsal midline [22].

Other interactions of Msx1

• However, the expression of three molecules involved in tooth initiation, Bmp4, Msx1, and Msx2, are absent from the presumptive chick dental lamina [23].
• These results are consistent with functional redundancy between Msx1 and Msx2 in dental mesenchyme and support a model whereby Msx and Dlx genes function in parallel within the dental mesenchyme during tooth initiation [8].
• Moreover, dental epithelium as well as beads soaked in FGF1, FGF2 or FGF8 induce Fgf3 expression in dental mesenchyme in an Msx1-dependent manner [8].
• In the latter case, the absence of Dlx5 rescues in part the Msx1-dependent defects in palate growth and elevation [24].
• We conclude that in the context of the tooth germ Msx1 is a component of the Shh signaling pathway that leads to Ptc induction [25].

Analytical, diagnostic and therapeutic context of Msx1

• Transfection assays in cell cultures with fragments from BP driving the expression of luciferase confirmed that only in the presence of the SMAD consensus site is Msx1 expression activated [18].
• In both fetal and neonatal digits, we find that both Msx1 and Msx2 are expressed during regeneration, but not during wound healing associated with proximal amputations where no regenerative response is observed [26].
• In vitro binding and co-immunoprecipitation analyses revealed that MAGE-D1 directly interacted with necdin via the homology domain and Msx1 (or Msx2) via the repeat domain [27].
• We have analyzed Msx1 expression in the mature mouse brain using in situ hybridization and beta-galactosidase activity in Msx1(nLacZ) mice [28].
• Specific reverse-transcription polymerase chain reaction (RT-PCR) Northern-blotting using riboprobes and primer extension analysis allowed to identify and sequence a mouse 2184-base Msx1 antisense transcript [29].

References