A role for Smad6 in development and homeostasis of the cardiovascular system

Smad proteins are intracellular mediators of signalling initiated by Tgf-be ta superfamily ligands (Tgf-beta s, activins and bone morphogenetic protein s (Bmps)). Smads 1, 2, 3, 5 and 8 are activated upon phosphorylation by spe cific type I receptors, and associate with the common partner Smad4 to trig ger transcriptional responses(1). The inhibitory Smads (6 and 7) are transc riptionally induced in cultured cells treated with Tgf-beta superfamily lig ands, and downregulate signalling in in vitro assays(2-7). Gene disruption in mice has begun to reveal specific developmental and physiological functi ons of the signal-transducing Smads. Here we explore the role of an inhibit ory Smad in vivo by targeted mutation of Madh6 (which encodes the Smad6 pro tein). Targeted insertion of a LacZ reporter demonstrated that Smad6 expres sion is largely restricted to the heart and blood vessels, and that Madh6 m utants have multiple cardiovascular abnormalities. Hyperplasia of the cardi ac valves and outflow tract septation defects indicate a function for Smad6 in the regulation of endocardial cushion transformation. The role of Smad6 in the homeostasis of the adult cardiovascular system is indicated by the development of aortic ossification and elevated broad pressure in viable mu tants. These defects highlight the importance of Smad6 in the tissue-specif ic modulation of Tgf-beta superfamily signalling pathways in vivo.