The human chordin gene encodes several differentially expressed spliced variants with distinct BMP opposing activities

During early embryogenesis of both vertebrates and invertebrates, antagonis m between bone morphogenetic proteins (BMPs) and several unrelated secreted factors including Chordin (Chd) is a general mechanism by which the dorso- ventral axis is established. High affinity binding of Chd sequesters the BM P ligands in the extracellular space, preventing interactions with their me mbrane receptors. Another level of regulation consists in processing of ver tebrate Chd or its Drosophila counterpart Sog by astacine metalloproteases like Xolloid-BMP-1/Tolloid, respectively, which releases an active BMP. Rec ently, it was shown that cleavage of Sog by Tolloid could generate novel BM P inhibitory activity and that sog is also capable of stimulation of BMP ac tivity in a tolloid-dependant way. Activity and/or cleavage of Chd/Sog are influenced by other secreted factors like twisted gastrulation. In this stu dy, we have cloned cDNAs of the human chordin gene (CHRD) and characterized alternative splice variants that code for C-truncated forms of the protein . We have found that CHRD is expressed in fetal as well as in adult tissues with relatively high levels in liver. cerebellum and female genital tract, suggesting functions in late embryogenesis and adult physiology. We also s how that spliced variants are present with specific patterns in various tis sues. When tested in an axis-duplication assay in Xenopus, we find that the se variants can antagonize BMP activity. Altogether, these results suggest that, in addition to processing by metalloproteases, alternative splicing ( AS) is another mechanism by which sub-products of CHRD can be generated to influence BMP activity in different developmental and physiological situati ons. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.