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    • Signaling pathways such as BMP FGF

    2022-09-24

    Signaling pathways such as BMP, FGF, and WNT are strongly involved in the process of endochondral ossification and Meckel's cartilage development [20]. Interestingly, absence of BMP antagonist, Noggin, in Meckel's cartilage, resulted in a phenotype, very similar to that of Setdb1 CKO [16]. To examine whether BMP signaling will change when Setdb1 is deleted in Meckel's cartilage, we have performed immunofluorescence against phospho-SMAD1/5/8. Phosho-SMAD1/5/8 positive AZ 10606120 dihydrochloride receptor were not seen near the perichondrium in control E14.5 sample (Fig. 4A), whereas abundant expression of phosho-SMAD1/5/8 was observed all over the Meckel's cartilage in Setdb1 mutant (Fig. 4B). To confirm the effect of Setdb1 on BMP signaling, we have checked for phospho-SMAD1/5/8-positive cells in Setdb1 siRNA treated ATDC5 cells. 48 h after transfection with Setdb1 siRNA, percentage of phospho-Smad1/5/8-positive cells was significantly higher compared to those treated with scramble siRNA (Fig. 4C–E). We next examined whether there were any changes in BMP ligands, receptors and antagonists in Setdb1 knockout ATDC5 cells. Bmp4, Bmpr1 and Bmpr2, were upregulated, and Noggin was downregulated when Setdb1 expression was decreased. However, BMP ligands, Bmp2 and Bmp7, were down regulated following Setdb1 siRNA treatment (Fig. 4F).
    Discussion The many roles of Setdb1, a histone methyltransferase responsible for epigenetic modification, remain unknown largely because conventional knockout mice for this gene die within 5.5 days after conception [7]. By knocking out the Setdb1 gene in mesenchymal cells, Yang et al. observed hypoplasia of long bones due to abnormalities in chondrocytes during endochondral ossification [8]. In the present study, we examined the roles of Setdb1 in Meckel's cartilage, which serves as the axis for mandibular formation, by using conditional knockout mice. Meckel's cartilage, which disappears in wild type mice, was enlarged in these knockout mice. This enlargement was considered to have resulted from the excessive proliferation and hyperplasia of chondrocytes. It was also suggested that the SMAD-mediated abnormal increase in BMP signaling might be involved in the hypertrophy of Meckel's cartilage. In the course of morphogenesis, where dynamic qualitative changes take place, tissue-specific gene expression is regulated via harmonized epigenetic alterations. Anomalies in this regulatory mechanism are responsible for the incidence of congenital disorders. In the maxillofacial area, especially, the genes for histone methylation enzymes WHSC1, NSD1 and MLL2 have been identified as the causative genes of Wolf-Hirschhorn syndrome of which primary symptoms include cardiac disorder and cleft palate, Sotos syndrome of which primary symptoms include macrocephaly and tall stature, and Kabuki syndrome of which primary symptoms include peculiar facial features such as palpebral fissure and cleft palate accompanied by mental retardation [21], [22]. These findings indicate a close correlation between abnormalities in the epigenetic regulatory mechanism and congenital disorders. When cleft palate occurs due to an overdose of retinoic acid, the expression of Whsc1 is known to decrease [23]. This implies the possibility that the decline in Whsc1 expression might be the direct cause of the condition. Thus, not only genetic alterations but also environmental factors change epigenomic information. For this reason, uncovering the role of histone methyltransferase may potentially contribute to the elucidation of birth defects. Similar to congenital disorders presumably associated with genetic and environmental factors, the occurrence and progress of cancer are also reported to be affected by epigenetic alterations because of genetic/environmental factors, or their interaction [1]. The Setdb1 gene is considered AZ 10606120 dihydrochloride receptor to be a type of oncogene, expressed profusely in carcinoma cells of liver cancer, lung cancer, prostate cancer, and breast cancer [24], [25], [26], [27]. When Setdb1 is knocked out from the carcinoma cells of lung, liver and prostate cancers displaying increased expression of Setdb1 by using siRNA, the growth of cancerous cells is suppressed [24], [25], [26]. This implies a close correlation between the overexpression of Setdb1 and the abnormal proliferation of carcinoma cells. Conversely, in Meckel's cartilage of our CKO mice, there was an increase in the proliferative capabilities of the cells. This phenomenon might partially be attributable to the SMAD-mediated augmentation of BMP signals in Meckel's cartilage in the CKO mice. BMP signals play a crucial role in chondrogenesis. Knocking out Noggin, a BMP antagonist, resulted in the hyperplasia of chondrocytes [28]. Furthermore, depriving only neural crest cells of the Noggin functions led to the enlargement of Meckel's cartilage as BMP signals surged [16]. The phenotype of these mice was similar to that of our CKO mice, thus suggesting that BMP signals were regulated by Setdb1 either directly or indirectly.