Recruitment and maintenance of tendon progenitors by TGFbeta signaling are essential for tendon formation.

Tendons and ligaments mediate the attachment of muscle to bone and of bone to bone to provide connectivity and structural integrity in the musculoskeletal system. We show that TGFbeta signaling plays a major role in the formation of these tissues. TGFbeta signaling is a potent inducer of the tendon progenitor (TNP) marker scleraxis both in organ culture and in cultured cells, and disruption of TGFbeta signaling in Tgfb2(-/-);Tgfb3(-/-) double mutant embryos or through inactivation of the type II TGFbeta receptor (TGFBR2; also known as TbetaRII) results in the loss of most tendons and ligaments in the limbs, trunk, tail and head.

Regulation of tendon differentiation by scleraxis distinguishes force-transmitting tendons from muscle-anchoring tendons.

The scleraxis (Scx) gene, encoding a bHLH transcription factor, is expressed in the progenitors and cells of all tendon tissues. To determine Scx function, we produced a mutant null allele. Scx-/- mice were viable, but showed severe tendon defects, which manifested in a drastically limited use of all paws and back muscles and a complete inability to move the tail.

Generation of transgenic tendon reporters, ScxGFP and ScxAP, using regulatory elements of the scleraxis gene.

Defects in tendon patterning and differentiation are seldom assessed in mouse mutants due to the difficulty in visualizing connective tissue structures. To facilitate tendon analysis, we have generated mouse lines harboring two different transgene reporters, alkaline phosphatase (AP) and green fluorescent protein (GFP), each expressed using regulatory elements derived from the endogenous Scleraxis (Scx) locus. Scx encodes a transcription factor expressed in all developing tendons and ligaments as well as in their progenitors.