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The Dmp1‐SOST Transgene Interacts With and Downregulates the Dmp1‐Cre Transgene and the Rosa Notch Allele
Author(s) -
Zanotti Stefano,
Canalis Ernesto
Publication year - 2016
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25405
Subject(s) - dmp1 , transgene , sclerostin , notch signaling pathway , genetically modified mouse , microbiology and biotechnology , cre recombinase , osteopetrosis , biology , wnt signaling pathway , chemistry , gene , genetics , immunology , viral matrix protein
Activation of Notch1 in osteocytes of Rosa Notch mice, where a loxP ‐flanked STOP cassette and the Nicd coding sequence were targeted to the reverse orientation splice acceptor ( Rosa ) 26 locus, causes osteopetrosis associated with suppressed Sost expression and enhanced Wnt signaling. To determine whether Sost downregulation mediates the effects of Notch activation in osteocytes, Rosa Notch mice were crossed with transgenics expressing Cre recombinase or SOST under the control of the dentin matrix protein ( Dmp ) 1 promoter. Dmp1‐SOST transgenics displayed vertebral osteopenia and a modest femoral cancellous and cortical bone phenotype, whereas hemizygous Dmp1‐Cre transgenics heterozygous for the Rosa Notch allele ( Dmp1‐Cre ; Rosa Notch ) exhibited osteopetrosis. The phenotype of Notch activation in osteocytes was prevented in Dmp1‐Cre ; Rosa Notch mice hemizygous for the Dmp1‐SOST transgene. The effect was associated with downregulated Notch signaling and suppressed Dmp1 and Rosa26 expression. To test whether SOST regulates Notch expression in osteocytes, cortical bone cultures from Dmp1‐Cre ; Rosa Notch mice or from Rosa Notch control littermates were exposed to recombinant human SOST. The addition of SOST had only modest effects on Notch target gene mRNA levels and suppressed Dmp1 , but not Cre or Rosa26 , expression. These findings suggest that prevention of the Dmp1‐Cre ; Rosa Notch skeletal phenotype by Dmp1‐SOST is not secondary to SOST expression but to interactions among the Dmp1‐SOST and Dmp1‐Cre transgenes and the Rosa26 locus. In conclusion, the Dmp1‐SOST transgene suppresses the expression of the Dmp1‐Cre transgene and of Rosa26 . J. Cell. Biochem. 117: 1222–1232, 2016. © 2015 Wiley Periodicals, Inc.