Msx1 and Msx2 function together in the regulation of primordial germ cell migration in the mouse. Sun J et al. (2016) Primordial germ cells (PGCs) are a highly migratory cell population that gives rise to eggs and sperm. Much is known about PGC specification, but less about the processes that control PGC migration. In this study, we document a deficiency in PGC development in embryos carrying global homozygous null mutations in Msx1 and Msx2, both immediate downstream effectors of Bmp signaling pathway. We show that Msx1(-/-);Msx2(-/-) mutant embryos have defects in PGC migration as well as a reduced number of PGCs. These phenotypes are also evident in a Mesp1-Cre-mediated mesoderm-specific mutant line of Msx1 and Msx2. Since PGCs are not marked in Mesp1-lineage tracing, our results suggest that Msx1 and Msx2 function cell non-autonomously in directing PGC migration. Consistent with this hypothesis, we noted an upregulation of fibronectin, well known as a mediator of cell migration, in tissues through which PGCs migrate. We also noted a reduction in the expression of Wnt5a and an increase in the expression in Bmp4 in such tissues in Msx1(-/-);Msx2(-/-) mutants, both known effectors of PGC development.//////////////////
NCBI Summary:
This gene encodes a member of the muscle segment homeobox gene family. The encoded protein functions as a transcriptional repressor during embryogenesis through interactions with components of the core transcription complex and other homeoproteins. It may also have roles in limb-pattern formation, craniofacial development, particularly odontogenesis, and tumor growth inhibition. Mutations in this gene, which was once known as homeobox 7, have been associated with nonsyndromic cleft lip with or without cleft palate 5, Witkop syndrome, Wolf-Hirschom syndrome, and autosomoal dominant hypodontia. [provided by RefSeq, Jul 2008]
General function
Nucleic acid binding, DNA binding, Transcription factor
Comment
Cellular localization
Nuclear
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Ovarian function
Germ cell migration, Oogenesis, Oocyte maturation, Early embryo development
Comment
Msx1 and Msx2 promote meiosis initiation. Le Bouffant R et al. The mechanisms regulating germ line sex determination and meiosis initiation are poorly understood. Here, we provide evidence for the involvement of homeobox Msx transcription factors in foetal meiosis initiation in mammalian germ cells. Upon meiosis initiation, Msx1 and Msx2 genes are strongly expressed in the foetal ovary, possibly stimulated by soluble factors found there: bone morphogenetic proteins Bmp2 and Bmp4, and retinoic acid. Analysis of Msx1/Msx2 double mutant embryos revealed a majority of undifferentiated germ cells remaining in the ovary and, importantly, a decrease in the number of meiotic cells. In vivo, the Msx1/Msx2 double-null mutation prevented full activation of Stra8, a gene required for meiosis. In F9 cells, Msx1 can bind to Stra8 regulatory sequences and Msx1 overexpression stimulates Stra8 transcription. Collectively, our data demonstrate for the first time that some homeobox genes are required for meiosis initiation in the female germ line.
BMP Signalling in the Human Fetal Ovary is Developmentally-regulated and Promotes Primordial Germ Cell Apoptosis. Childs AJ et al. Primordial Germ Cells (PGCs) are the embryonic precursors of gametes in the adult organism, and their development, differentiation and survival is regulated by a combination of growth factors collectively known as the germ cell niche. Although many candidate niche components have been identified through studies on mouse PGCs, the growth factor composition of the human primordial germ cell niche has not been studied extensively. Here we report a detailed analysis of the expression of components of the BMP signalling apparatus in the human fetal ovary, from post-migratory PGC proliferation to the onset of primordial follicle formation. We find developmentally-regulated and reciprocal patterns of expression of BMP2 and BMP4, and identify germ cells to be the exclusive targets of ovarian BMP signalling. By establishing long term cultures of human fetal ovaries in which PGCs are retained within their physiological niche, we find that BMP4 negatively regulates post-migratory PGC numbers in the human fetal ovary by promoting PGC apoptosis. Finally, we report expression of both MSX1 and MSX2 in the human fetal ovary, and reveal a selective up-regulation of MSX2 expression in human fetal ovary in response to BMP4, suggesting this gene may act as a downstream effector of BMP-induced apoptosis in the ovary, as in other systems. These data reveal for the first time growth factor regulation of human PGC development in a physiologically relevant context, and have significant implications for the development of cultures systems for the in vitro maturation of germ cells, and their derivation from pluripotent stem cells.
Suppression of the transcription factor MSX1 gene delays bovine preimplantation embryo development in vitro. Tesfaye D et al. This study was conducted to investigate the effect of suppressing transcription factor gene MSX1 on the development of in vitro produced bovine oocytes and embryos and identify its potential target genes regulated by this gene. Injection of long double stranded RNA (LdsRNA) and small interfering RNA (siRNA) at germinal vesicle (GV) stage oocyte reduced MSX1 mRNA expression by 73 and 37% respectively at metaphase II (MII) stage compared to non-injected controls. Similarly, injection of the same anti-sense oligomers at zygote stage reduced MSX1 mRNA expression by 52 and 33% at 8-cells stage compared with non-injected controls. Protein expression was also reduced in LdsRNA and siRNA injected groups compared with non-injected controls at both stages. Blastocysts rates were 33, 28, 20 and 18% in non-injected control, scrambled RNA (scRNA), LdsRNA and siRNA injected groups respectively. Cleavage rates were also significantly reduced in Smartpool small interfering RNA (SpsiRNAs) injected group (53.76%) compared to scRNA (57.76%) and non-injected control (61%). Large scale gene expression analysis showed that 135 genes were differentially regulated in SpsiRNAs injected group compared with non-injected controls of which 54 and 81 were down and up regulated, respectively due to suppression of MSX1. Additionally, sequence homology mapping and gene enrichment analysis with known human pathway information identified several functional modules that were affected due to suppression of MSX1. In conclusion, suppression of MSX1 affects oocyte maturation, embryo cleavage rate and the expression of several genes suggesting its potential role in the development of bovine preimplantation embryos.