MSH/Msx genes
MSH/Msx genes are a family of genes that encode proteins characterized by a highly conserved homeodomain, distinct from the classical Antennapedia type homeodomain. These genes have been identified across a range of metazoans, including vertebrates and fruit flies, and are crucial for tissue interactions during organ development, particularly between epithelial and mesenchymal cells. In fruit flies, MSH is involved in the early formation of neural stem cells, while in vertebrates, MSH expression begins in the ectoderm and later shifts to the mesoderm, indicating similar roles in development across species.
In mice, the Msx gene family consists of three members—Msx1, Msx2, and Msx3—that share a high degree of homology. Msx1 and Msx2 are expressed in various tissues during embryogenesis and are essential for processes such as neural tube and craniofacial development. Disruptions in these genes can lead to significant morphological abnormalities. Additionally, the expression of Msx2 is influenced by bone morphogenetic protein (BMP) signaling, involving complex regulatory elements that are conserved among mammals but may not be present in other vertebrates.
Overall, the MSH/Msx genes are integral to understanding developmental biology and the molecular mechanisms that guide tissue formation and differentiation across different species.
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MSH/Msx genes
SIGNIFICANCE: The muscle segment homeobox MSH/Msx genes encode a family of proteins with a distinct and highly conserved homeodomain that is divergent from the classical Antennapedia type homeodomain. They have been identified in a wide variety of metazoans from vertebrates to fruit flies and participate in inductive tissue interactions that underlie organogenesis, particularily interactions between epithelial and mesenchymal cells (mesodermal cells that give rise to connective tissue).
In the fruit fly, Drosophila, expression of MSH precedes the formation of neural stem cells in the lateral lateral regions of the early central nervous system. In vertebrates, MSH is also first expressed in ectoderm, followed by expression in mesoderm. A similar temporal and spatial pattern of gene activity occurs in flies involving a switch from ectodermal to mesodermal expression, suggesting that vertebrate and DrosophilaMSH play similar developmental roles.
The mouse Msx genes consist of three physically unlinked members, Msx1, Msx2, and Msx3, which share 98 percent homology in the homeodomain. Msx1 and Msx2 are expressed during embryogenesis, in overlapping patterns, at many sites of epithelial-mesenchymal inductive interactions, such as limb and tooth buds, heart, branchial arches, and craniofacial processes, but also in the roof plate and adjacent cells in the dorsal neural tube and neural crests. Msx3, however, is expressed exclusively in the dorsal aspect of the neural tube in the mouse, caudally to the isthmus 7 and 8.
The vertebrate homeobox genes Msx1 and Msx2 are related to the DrosophilaMSH gene and are expressed in a variety of tissues during embryogenesis. In mouse embryos, the muscle segment homeobox genes, Msx1 and Msx2, are expressed during critical stages of neural tube, neural crest, and craniofacial development. Msx1 is required during the early stages of neurulation, since antisense RNA interference with Msx1 expression produces hypoplasia of the maxillary, mandibular, and frontonasal prominences, in addition to eye, somite, and neural tube abnormalities. Eye defects consist of enlarged optic vesicles, which may ultimately result in micropthalmia. Msx2 antisense oligodeoxynucleotides produce similar malformations as those targeting Msx1, with the exception that there is an increase in number and severity of neural tube and somite defects. Embryos injected with the combination of Msx1 and Msx2 antisense oligodeoxynucleotides show no novel abnormalities.
In the Msx1-/-:Msx2-/- double mutant, defects are limited to the anterior part of the limb bud, even though Msx1 and Msx2 are expressed over the whole apical region of the limb bud. A study identified a DNA enhancer of Msx2 that was activated by bone morphogenetic protein (BMP) signaling. The BMP-responsive region of Msx2 consists of a core element, required generally for BMP-dependent expression, and ancillary elements that mediate signaling in diverse developmental settings. Analysis of the core element identified two classes of functional sites: GCCG sequences related to the consensus binding site of Mad/Smad-related BMP signal transducers; and a single TTAATT sequence, matching the consensus site for Antennapedia superclass homeodomain proteins. Chromatin immunoprecipitation and mutagenesis experiments indicate that the GCCG sites are direct targets of BMP-restricted Smads. The GCCG sites were not sufficient for BMP responsiveness in mouse embryos, since the TTAATT sequence was also required. DNA sequence comparisons reveal this element is highly conserved in Msx2 promoters from mammals but is not found in other vertebrates or nonvertebrates. Despite this lack of conservation outside mammals, the Msx2 BMP-responsive element serves as an accurate readout of Dpp signaling in a distantly related fruit fly, Drosophila. Strikingly, in Drosophila embryos, as in mice, both TTAATT and GCCG sequences are required for Dpp responsiveness, showing that a common cis-regulatory apparatus could mediate the transcriptional activation of BMP-regulated genes in widely divergent organisms.
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