Abstract
Lateral Meningocele or Lehman Syndrome (LMS) is associated with NOTCH3 mutations causing deletions of the PEST domain and a gain-of-NOTCH3 function. We demonstrated that Notch3(em1Ecan) mice harboring Notch3 mutations analogous to those found in LMS are osteopenic because of enhanced bone resorption. To determine the contribution of specific cell lineages to the phenotype, we created a conditional-by-inversion (Notch3(COIN)) model termed Notch3(em2Ecan) in which Cre recombination generates a Notch3(INV) allele expressing a NOTCH3 mutant lacking the PEST domain. Germ line Notch3(COIN) inversion caused osteopenia and phenocopied the Notch3(em1Ecan) mutant, validating the model. To induce the mutation in osteocytes, smooth muscle and endothelial cells, Notch3(COIN) mice were bred with mice expressing Cre from the Dmp1, Sm22a and Cdh5 promoters, respectively, creating experimental mice harboring Notch3(INV) alleles in Cre-expressing cells and control littermates harboring Notch3(COIN) alleles. Notch3(COIN) inversion in osteocytes led to femoral and vertebral cancellous bone osteopenia, whereas Notch3(COIN) inversion in mural Sm22a or endothelial Cdh5-expressing cells did not result in a skeletal phenotype. In conclusion, introduction of the LMS mutation in osteocytes but not in vascular cells causes osteopenia and phenocopies Notch3(em1Ecan) global mutant mice.