Trends in Genetics
ReviewThe function and evolution of Msx genes: pointers and paradoxes
Abstract
The Msx genes of vertebrates comprise a small family of chromosomally unlinked homeobox-containing genes related to the Drosophila gene muscle-segment homeobox (msb). Despite their ancient pedigree, the Msx genes are expressed in a range of vertebrate-specific tissues, including neural crest, cranial sensory placodes, bone and teeth. They are active in numerous systems, which have been used as models to study pattern formation and tissue interaction, and are, therefore, attracting a growing interest among developmental biologists. But beyond their presumed role as transcription factors, we do not know what their functions are in the cell or the embryo. Here, I review recent evidence that is beginning to address this problem and might eventually increase our understanding of how the vertebrate embryo has evolved.
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Cited by (312)
Bone remodelling marker expression in grafted and ungrafted sheep tooth extraction sockets: A comparative randomised study
2023, Archives of Oral BiologyTo compare key markers of bone remodelling in a sheep tooth extraction model for sockets left to heal naturally or grafted with the bovine-derived xenograft Bio-Oss® covered with a collagen Bio-Gide® membrane.
Right side premolar teeth were removed from thirty Romney-cross ewes. Standardised sockets in each sheep were randomly allocated treatments, a grafted test and an empty control. At 4-, 8- and 16-weeks sheep were euthanized and tissue collected (N = 10/group). RANK, RANKL and OPG immunohistochemical analysis was performed (n = 3). RANK, RANKL, OPG, COL1A1, TIMP3, SP7 and MSX2 mRNA expression levels were determined using RT2-qPCR assays (n = 3).
Histologically, more new woven bone was observed in the test group at all time points. Strong RANK and RANKL expression was found in both groups; at all time points with stronger RANK staining in the test group at 8 and 16 weeks. Strong OPG staining was localized to both osteoblasts and connective tissues. RANK receptor mRNA was expressed at a lower level in the test group (−4.26-fold; p = 0.02) at 4 weeks and SP7 at 16 weeks (−2.89-fold; p = 0.04). COL1A1 and TIMP3 mRNA expression increased significantly over time in the control group (p = 0.045, F = 5.4 and p = 0.003, F = 42.2 respectively).
Socket healing over time was comparable. The sheep tooth extraction model was found to be suitable for the evaluation of changes in the alveolar bone at the molecular level.
Msx1 is essential for proper rostral tip formation of the mouse mandible
2023, Biochemical and Biophysical Research CommunicationsThe right and left mandibular processes derived from the first branchial arch grow toward the midline and fuse to create the rostral tip region of the mandible during mandibular development. Severe and mild cases of failure in this process results in rare median cleft of the lower lip and cleft chin, respectively. The detailed molecular mechanisms of mandibular tip formation are unknown. We hypothesize that the Msx1 gene is involved in mandibular tip development, because Msx1 has a central role in other craniofacial morphogenesis processes, such as teeth and the secondary palate development. Normal Msx1 expression was observed in the rostral end of the developing mandible; however, a reduced expression of Msx1 was observed in the soft tissue of the mandibular tip than in the lower incisor bud region. The rostral tip of the right and left mandibular processes was unfused in both control and Msx1-null (Msx1−/−) mice at embryonic day (E) 12.5; however, a complete fusion of these processes was observed at E13.5 in the control. The fused processes exhibited a conical shape in the control, whereas the same region remained bifurcated in Msx1−/−. This phenotype occurred with 100% penetrance and was not restored at subsequent stages of development. Furthermore, Meckel's cartilage in addition to the outline surface soft tissues was also unfused and bifurcated in Msx1−/− from E14.5 onward. The expression of phosho-Smad1/5, which is a mediator of bone morphogenetic protein (Bmp) signaling, was downregulated in the mandibular tip of Msx1−/− at E12.5 and E13.5, probably due to the downregulated Bmp4 expression in the neighboring lower incisor bud. Cell proliferation was significantly reduced in the midline region of the mandibular tip in Msx1−/− at the same developmental stages in which downregulation of pSmad was observed. Our results indicate that Msx1 is indispensable for proper mandibular tip development.
Msx1 cooperates with Runx1 for inhibiting myoblast differentiation
2021, Protein Expression and PurificationMyogenesis is an important and complicated biological process, especially during the process of embryonic development. The homeoprotein Msx1 is a crucial transcriptional repressor of myogenesis and maintains myogenic precursor cells in an undifferentiated, proliferative state. However, the molecular mechanism through which Msx1 coordinates myogenesis remains to be elucidated. Here, we determine the interacting partner proteins of Msx1 in myoblast cells by a proteomic screening method. Msx1 is found to interact with 55 proteins, among which our data demonstrate that the cooperation of Runt-related transcription factor 1 (Runx1) with Msx1 is required for myoblast cell differentiation. Our findings provide important insights into the mechanistic roles of Msx1 in myoblast cell differentiation, and lays foundation for the myogenic differentiation process.
In silico characterization and structural modeling of a homeobox protein MSX1 from Homo sapiens
2021, Informatics in Medicine UnlockedMSX1 protein, a homeobox transcriptional regulator plays a significant role in various developmental processes of the mammalian system such as limb-pattern formation, craniofacial development, in particular, odontogenesis, and tumor growth inhibition. Several studies have been performed on MSX1 at the genomic and transcriptomic levels. However, there is a lack of information on its structural and conformational aspects.
For better understanding of the molecular mechanism of MSX1, the present study aims to conduct a detailed in-silico analysis of this protein in terms of its physicochemical properties, secondary and tertiary structure predictions, interacting partners, and phylogenetic relationship with other orthologs.
The sequence of the MSX1 protein from Homo sapiens was retrieved in the FASTA format from the National Center for Biotechnology Information (NCBI). The standard bioinformatic tools were further used to characterize and model the structure of this protein.
The in-silico characterization of MSX1 revealed that it is a basic, non-polar, and thermostable globular protein mainly localized in the nucleus. This protein is extremely rigid due to the presence of high proline content. The phylogenetic and synteny analysis revealed that the gene is highly conserved at the level of the amino acid sequences, but underwent several modifications at the genomic level in the course of evolution possibly to attain the diverse function. Major part of this protein is a random coil, making it suitable for interaction with other proteins. Subcellular localization and protein-protein interaction suggested that the protein may act as a secretory protein and play a crucial role in regulating several developmental processes. Docking analysis suggested that the MSX1 protein may interact with other proteins and form complexes to carry out its function.
The structural characterization of this protein will help to better understand its molecular mechanism of action. In addition, the predicted 3-D model would act as a base for further understanding of the protein's other functional potential.
The C-terminal region including the MH6 domain of Msx1 regulates skeletal development
2020, Biochemical and Biophysical Research CommunicationsMSX1 is a causative gene for oligodontia in humans. Although conventional Msx1-deficient mice die neonatally, a mutant mouse lacking the C-terminus MH6 domain of MSX1 (Msx1ΔMH6/ΔMH6) showed two different phenotypes; newborn homozygotes with cleft palates died neonatally, whereas those with thin palates remained alive and had craniofacial dysplasia and growth retardation compared with wild-type mice, with most mice dying by the age of 4–5 weeks. In a previously reported case of human oligodontia caused by a heterozygous defect of the Msx1 MH6 domain, a small foramen was observed on the occipital bone. The aim of this study was to test the hypothesis that the Msx1 MH6 domain is involved in bone formation in vivo. In Msx1ΔMH6/ΔMH6 mice, cranial suture fusion was delayed at embryonic day 18.5, and the anteroposterior cranial diameter was smaller and long bone length was decreased at 3 weeks of age. The femoral epiphysis showed no change in the trabecular number, but decreased bone mass, bone density, and trabecular width in Msx1ΔMH6/ΔMH6 mice. In addition, cancellous bone mass was reduced and the cartilage layer in the growth plate was thinner in Msx1ΔMH6/ΔMH6 mice. The mRNA expression levels of major osteoblast and chondrocyte differentiation marker genes were decreased in Msx1ΔMH6/ΔMH6 mice compared with wild-type mice. These findings suggest that the C-terminal region including the MH6 domain of MSX1 plays important roles not only in tooth development and palatal fusion, but also in postnatal bone formation.
Loss of homeoprotein Msx1 and Msx2 leading to athletic and kinematic impairment related to the increasing neural excitability of neurons in aberrant neocortex in mice
2019, Biochemical and Biophysical Research CommunicationsAlthough homeoproteins Msx1 and Msx2, the cell-specific transcription regulators, have been proven to play multiple roles in the embryogenesis of bone, muscle and tooth, the functions and mechanisms of Msx1 and Msx2 in the development of the central nervous system of mice after birth are not clear because of the death of Msx1 and Msx1/2 germline-deleted embryo at late gestation of mouse. In current research, Nestin-Cre mice was introduced to generate the central nervous system-specific knockout mice (Nestin-Cre;Msx1,Msx2fl/fl). We found that besides the falling of the body mass and the brain volume, the cortical tissue sections and staining showed the decreasing thickness of layer II-IV and declining number of vertebral cells in layer V resulting from Msx1/2 deletion. In addition, electrophysiological tests revealed the aberrant action potential parameters of deep pyramidal neurons in Nestin-Cre;Msx1,2 fl/fl mice, which may be related with the ethology impairment displayed in further experiments. We discovered Nestin-Cre;Msx1,2 fl/fl mice had severe impairment in their athletic ability and kinematic learning ability in rotate test, and exhibited hyperactivity in open-field test. Above all, our results revealed that deletion of homeoproteins Msx1 and Msx2 could lead to behavioral disorders and suggested that Msx1 and Msx2 played a crucial role in regulating the development and function of the neocortex. In addition, our current research provided a new mouse model for understanding the pathogenesis of human central nervous system disease.