EXT genes are differentially expressed in bone and cartilage during mouse embryogenesis

Hereditary multiple exostoses (HME) is a genetically heterogeneous disease characterized by the development of bony protuberances at the ends of all l ong bones. Genetic analyses have revealed HME to be a multigenic disorder l inked to three loci on chromosomes 8q24 (EXT1), 11p11-13 (EXT2), and 19p (E XT3). The EXT1 and EXT2 genes have been cloned and defined as glycosyltrans ferases involved in the synthesis of heparan sulfate, EST database analysis has demonstrated additional gene family members, EXT-like genes (EXTL1, EX TL2, and EXTL3), not associated with a HME locus. The mouse homologs of EXT 1 and EXT2 have also been cloned and shown to be 99% and 95% identical to t heir human counterparts, respectively, Here, we report the identification o f the mouse EXTL1 gene and show it is 74% identical to the human EXTL1 gene . Expression studies of all three mouse EXT genes throughout various stages of embryonic development were carried out and whole-mount in situ hybridiz ation in the developing limb buds showed high levels of expression of all t hree EXT genes, However, in situ hybridization of sectioned embryos reveale d remarkable differences in expression profiles of EXT1, EXT2, and EXTL1, T he identical expression patterns found for the EXT1 and EXT2 genes support the recent observation that both proteins form a glycosyltransferase comple x, We suggest a model for exostoses formation based on the involvement of E XT1 and EXT2 in the Indian hedgehog/parathyroid hormone-related peptide (PT HrP) signaling pathway, an important regulator of the chondrocyte maturatio n process. (C) 2000 Wiley-Liss, Inc.