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  • BMP signals play pivotal roles in the

    2022-05-23

    BMP signals play pivotal roles in the various processes of chondrogenesis [12], [13]. At early stages of chondrogenesis, BMP signaling regulates the differentiation of mesenchymal Dioscin into chondrocytes via the induction of Sox9[29]. The loss of Noggin, a BMP antagonist, results in the overgrowth of cartilage [28], and the overexpression of BMP ligands and BMP receptors leads to the enlargement of bone structures, including cartilage [14], [30]. Therefore, BMP signals and their increase are highly likely to be closely related to the growth of cartilage. With regard to the correlation between Meckel's cartilage and BMP signals, knocking out Noggin, only in neural crest cell derived cells, did not result in a decrease in Meckel's cartilage. Instead, Meckel's cartilage enlarged, as in CKO mice, occupying a large part of the lower mandible [16]. In Meckel's cartilage of the CKO mice and ATDC5 cells where Setdb1 was knocked down with siRNA, the expression of phosphorylated Smad1/5/8 was strongly activated. This suggested that the enlargement of Meckel's cartilage by Setdb1 might be attributable to the augmentation of BMP signals. We examined ATDC5 cells to see if the loss of Setdb1 alters BMP ligands, receptors and antagonists involved in BMP signaling. We observed that the levels of Bmp4, Bmpr1, and Bmpr2 increased, whereas the expression of Noggin decreased. Setdb1 is believed to regulate gene expression by H3K9 [6]. It may, therefore, be directly regulating any or several of Bmp, Bmprs and Noggin functions. The chondrocytes in Meckel's cartilage of the CKO mice were significantly larger than those in control mice due to continuous hypertrophy. The cells in the middle of Meckel's cartilage managed to differentiate into hypertrophic chondrocytes, but ceased to differentiate thereafter and ultimately became degenerate and disappeared [9,10,20]. BMP signals function to suppress the differentiation of hypertrophic chondrocytes and advance the enlargement of chondrocytes [11]. The overexpression of BMP signaling in the Setdb1 CKO mice was probably responsible for the enlargement of chondrocytes. In the mice where Setdb1 was knocked out in mesenchymal cells, a phenomenon similar to that observed in the Setdb1 CKO mice occurred, with chondrocytes exhibiting enlargement during endochondral ossification [8]. This also demonstrated the close correlation between Setdb1 and the enlargement of chondrocytes.
    Acknowledgments We thank Dr. Y. Shinkai and Dr. S. Iseki for providing the mice harboring the floxed Setdb1 allele and Wnt1-Cre mice, respectively. We also thank Dr. M. Nakamura and Dr. S. Iseki for helpful comments, and Dr. S. Ryu and the members of the Department of Maxillofacial Orthognathics, Tokyo Medical and Dental University for technical advice. This work was supported by KAKENHI (24792278, 26861773, 16K11780) to NH.
    Introduction Cleft lip with or without palate (CL/P) is a multifactorial disease caused by the interaction of genetic and environmental factors [1]. There are several known candidate genes for CL/P. The best candidates, in which mutations have been reported, are IRF6, SUMO1, MSX1, FGFR1, FGFR2, FGF8, BMP4, and TBX1[1], [2], [3]. Genome-wide association studies have reported several loci strongly associated with CL/P, for example the “gene desert” region on chromosome 8q24, VAX1 at 10q25, and VOG at 17q22 [1]. However, there are also studies that have begun to provide data on environmental risks of CL/P. Maternal smoking; some specific teratogens, for example valproic acid; nutritional factors, such as folate deficiency; and exposure to maternal alcohol consumption have all been suggested as risk factors for cleft palate [1]. Retinoic acid (RA) is the one of the environmental factors for which both deficiency and overdose cause CL/P in mice and humans [4]. The mechanisms by which RA induces cleft palate have been studied from several points of view. At the time of palatal shelf outgrowth, overdose of RA upregulates the cyclin-dependent kinase inhibitor p21 and hypophosphorylates the RB1 protein, resulting in an inhibition of mesenchymal cell proliferation in the palate [5], [6]. Moreover, RA inhibits mesenchymal proliferation of palatal shelves through down-regulation of Bmp2 expression [7]. At the time of shelf elevation, RA prevents tongue withdrawal through down-regulation of Tbx1, a candidate gene for DiGeorge syndrome, in which CL/P is one of the phenotypic features. This might physically prevent the elevation of the palatal shelves [8]. Prior to elevation, excess of RA may directly suppress collagen synthesis through binding to retinoic acid response element sites in the α2(I) collagen promoter region, thus hampering extracellular matrix production [9]. During palatal shelf elevation, RA inhibits the synthesis of matrix metalloproteinases in the extracellular matrix (ECM) of the palatal mesenchymal cells and stimulates the expression of tissue inhibitors of matrix metalloproteinases [10]. This might lead to reduced remodeling of the ECM and impaired elevation of the palatal shelves. In the period of palatal shelf fusion, excess of RA reduced the expression of filopodia and chondroitin sulfate proteoglycans in peridermal cells through alteration of growth factor signaling, such as that mediated by PDGF and TGF-β3 [11], [12]. The filopodia and chondroitin sulfate proteoglycans of medial edge epithelia mediate adhesion, so their reduced expression interferes with palatal shelf adherence. Taken together, these data imply that RA is fundamental for palate development.