Little is known about the genesis and patterning of tendons and other connective tissues, mostly owing to the absence of early markers We have found that Scleraxis, a bHLH transcription factor, is a highly specific marker for all the connective tissues that mediate attachment of muscle to bone in chick and mouse, including the limb tendons, and show that early scleraxis expression marks the progenitor cell populations for these tissues In the early limb bud, the tendon progenitor population is found in the superficial proximomedial mesenchyme Using the scleraxis gene as a marker we show that these progenitors are induced by ectodermal signals and restricted by bone morphogenetic protein (BMP) signaling within the mesenchyme Application of Noggin protein antagonizes this endogenous BMP activity and induces ectopic scleraxis expression However, the presence of excess tendon progenitors does not lead to the production of additional or longer tendons, indicating that additional signals are required for the final formation of a tendon Finally, we show that the endogenous expression of noggin within the condensing digit cartilage contributes to the induction of distal tendons

Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments

https://www.oarsijournal.com/article/S1063-4584(99)90306-0/pdf

Cellular interactions and signaling in cartilage development.

The proper development of the musculoskeletal system in the tetrapod limb requires the coordinated development of muscle, tendon and cartilage. This paper examines the morphogenesis of muscle and tendon in the developing avian hind limb. Based on a developmental series of embryos labeled with myosin and tenascin antibodies in whole mount, an integrative description of the temporal sequence and spatial pattern of muscle and tendon morphogenesis and their relationship to cartilage throughout the chick hind limb is presented for the first time. Anatomically distinct muscles arise by the progressive segregation of muscle: differentiated myotubes first appear as a pair of dorsal and ventral muscle masses; these masses subdivide into dorsal and ventral thigh, shank and foot muscle masses; and finally these six masses segregate into individual muscles. From their initial appearance, most myotubes are precisely oriented and their pattern presages the pattern of future, individual muscles. Anatomically distinct tendons emerge from three tendon primordia associated with the major joints of the limb. Contrary to previous reports, comparison of muscle and tendon reveals that much of their morphogenesis is temporally and spatially closely associated. To test whether reciprocal muscle-tendon interactions are necessary for correct muscle-tendon patterning or whether morphogenesis of each of these tissues is autonomous, two sets of experiments were conducted: (1) tendon development was examined in muscleless limbs produced by coelomic grafting of early limb buds and (2) muscle development was analyzed in limbs where tendon had been surgically altered. These experiments demonstrate that in the avian hind limb the initial morphogenetic events, formation of tendon primordia and initial differentiation of myogenic precursors, occur autonomously with respect to one another. However, later morphogenetic events, such as subdivision of muscle masses and segregation of tendon primordia into individual tendons, do require to various degrees reciprocal interactions between muscle and tendon. The dependence of these later morphogenetic events on tissue interactions differs between different proximodistal regions of the limb.

Muscle and tendon morphogenesis in the avian hind limb

Elements of the vertebrate skeleton are initiated as cell condensations, collectively termed the 'membranous skeleton' whether cartilages or bones by Gruneberg (1963). Condensations, which were identified as the basic cellular units in a recent model of morphological change in development and evolution (Atchley and Hall 1991) are reviewed in this paper. Condensations are initiated either by increased mitotic activity or by aggregation of cells towards a centre. Prechondrogenic (limb bud) and preosteogenic (scleral ossicle) condensations are discussed and contrasted. Both types of skeletogenic condensations arise following epithelial-mesenchymal interactions; condensations are identified as the first cellular product of such tissue interactions. Molecular characteristics of condensations are discussed, including peanut agglutinin lectin, which is used to visualize prechondrogenic condensations, and hyaluronan, hyaladherins, heparan sulphate proteoglycan, chondroitin sulphate proteoglycan, versican, tenascin, syndecan, N-CAM, alkaline phosphatase, retinoic acid and homeo-box-containing genes. The importance for the initiation of chondrogenesis or osteogenesis of upper and lower limits to condensation size and the numbers of cells in a condensation are discussed, as illustrated by in vitro studies and by mutant embryos, including Talpid3 in the chick and Brachypod, Congenital hydrocephalus and Phocomelia in the mouse. Evidence that genes specific to the skeletal type are selectively activated at condensation is discussed, as is a recent model involving TGF-beta and fibronectin in condensation formation. Condensations emerge as a pivotal stage in initiation of the vertebrate skeleton in embryonic development and in the modification of skeletal morphology during evolution.

The membranous skeleton: the role of cell condensations in vertebrate skeletogenesis.

Tenascin and fibronectin are two major extracellular matrix glycoproteins. They both consist of large disulfide-linked subunits composed of multiple structural domains. More than half of each molecule consists of so-called fibronectin type III repeats, but the other domains differ. Fibronectin is a dimer, whereas tenascin is a hexamer. Often fibronectin and tenascin are colocalized in tissues, but the occurrence of tenascin is much more restricted when compared with fibronectin. Tenascin is transiently expressed in many developing organs such as connective tissues, the mesenchyme of epithelial organs, and also the central and peripheral nervous systems, and it reappears in the stroma of many tumors. The distinctive and highly regulated expression of tenascin has provoked interest in trying to identify possible functions of tenascin in cell-cell and cell-substratum adhesion, cell migration, growth, and cell differentiation during morphogenesis.

What distinguishes tenascin from fibronectin

The extracellular matrix architecture relating to myotendinous pattern formation in the distal part of the developing chick limb: An ultrastructural, histochemical and immunocytochemical analysis

J.M. Genis-Galvez

Papers

The extracellular matrix architecture relating to myotendinous pattern formation in the distal part of the developing chick limb: An ultrastructural, histochemical and immunocytochemical analysis