Involvement of long- and short-range signalling during early tendon development

Abstract

Tendons connect muscle to skeletal elements. Although tendons have been shown to originate from the lateral plate mesoderm, very little is known at the molecular level about how they are formed. We have found that two genes, Follistatin and Eph-A4, are expressed in regions associated with tendon formation in developing chick limbs. Follistatin is expressed near the tip of the digits and subsequently around the tendon, whereas Eph A4 transcripts were localized in a slightly more proximal region and later in the body of the tendon. Previous work has demonstrated that application of TGFbeta1 or TGFbeta2 to inter-digital regions or the removal of ectoderm in the foot plate induces ectopic cartilage formation, while removal of ectoderm or application of FGF to tips of developing digits leads to truncation. Here we show that TGFbeta1 or removal of ectoderm is also able to induce the expression of both Eph-A4 and Follistatin and that manipulations that cause truncations affect these genes. Thus cartilage and tendon development appear to be coordinated. Ectopic application of recombinant human Follistatin, an antgaonist of certain TGFbeta super-family proteins including Activin and Bmp-4, results in the loss of tendon, implicating signalling by TGFbeta super-family in the development of tendon during chick embryogenesis. Signalling by TGFbeta family members, antagonised by Noggin is known to regulate skeletal development. Thus we suggest that parallel pathways govern both skeletal and tendon patterning.

Three-Dimensional Culture and Transforming Growth Factor Beta3 Synergistically Promote Tenogenic Differentiation of Equine Embryo-Derived Stem Cells

“…More robust markers of tenocytes include Scleraxis (SCX), Tenomodulin (TNMD), Tenascin-C (TNC), Cartilage oligomeric matrix protein (COMP), and Thrombospondin-4 (THBS4), which are not only collectively expressed in tendons, but individually also present in other tissue types. [22][23][24][25][26] Developmental studies have also implicated genes such as Six1/2, Eph-A4, Eya1/2, Egr1/2, and Mohawk (Mkx), 25,[27][28][29][30] although it has not been established whether these genes show temporally restricted expression in tendon tissue.…”

Mechanical Load and BMP Signaling During Tendon Repair: A Role for Follistatin?

“…Because we have not analyzed all BMPs, antagonists, and receptors, it is possible other factors within the BMP signaling system play important roles that would change our perception. Our choice of genes was governed by our previous finding of effects of exogenous GDFs and the fact that follistatin is expressed around the forming tendon in chicken embryos, where exogenous follistatin inhibits tendon formation [4]. BMPR1b was chosen because it is known to interact with GDF-5, which does not bind to BMPR1a [13].…”

Signals regulating tendon formation during chick embryonic development

“…The literature contains reports (sometimes anecdotal) that genes are located in tendons during embryonic limb development. The tyrosine kinase receptor, Eph-A4 (Patel et al, 1996;D'Souza and Patel, 1999), the transforming growth fac- (Hurle et al, 1989;Birk and Mayne, 1997), mouse (Niederreither et al, 1995), human (Waggett et al, 1998) E12 death due to vascular defects (Lohler et al, 1984) Type III collagen Chick (Birk and Mayne, 1997), mouse (Niederreither et al, 1995) Abnormal type I collagen fibrillogenesis (Liu et al, 1997) Type V collagen Chick (Birk and Mayne, 1997), mouse (Imamura et al, 2000) Abnormal type I collagen fibrillogenesis (Andrikopoulos et al, 1995) Type VI collagen Chick (Ros et al, 1995), mouse (Watanabe et al, 1997).…”

“…Chick (D'Souza and Patel, 1999) E9 death (Winnier et al, 1995) Fgf8 Chick (Edom-Vovard et al, 2001a) Early death (Meyers et al, 1998) Fgf18 Chick (Ohuchi et al, 2000) Bone phenotype (Ohbayashi et al, 2002;Liu et al, 2002) Follistatin Chick (D'Souza andPatel, 1999) Multiple defects and perinatal death (Matzuk et al, 1995) Tgf␤2 Chick (Merino et al, 1998) and mouse (Pelton et al, 1989) Widespread defects including vascular but tendon not reported (Dunker and Krieglstein, 2000) Transmembrane proteins…”

“…This differential behaviour of distal tendons vs. intermediate and proximal tendons, in the absence of muscles can be explained by the fact that distal limb tendons form independently and then gradually join to intermediate tendons to generate the complete pattern of tendon (Kardon, 1998). In addition, there is not much muscle at the digit level and autopod tendon formation is more associated with cartilage development (Hurle et al, 1990;D'Souza and Patel, 1999;Schweitzer et al, 2001). Inhibition of digit cartilage formation by means of apical ectodermal ridge (AER) removal leads abnormal tendons, while ectopic digits generated by interdigital ectoderm removal resulted in induction of ectopic tendons, indicating that the presence of a cartilage element is sufficient for induction of a digit tendon (Hurle et al, 1990).…”