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 morphological and functional evolution of appendages has played a crucial role in the adaptive radiation of tetrapods, arthropods and winged insects. The origin and diversification of fins, wings and other structures, long a focus of palaeontology, can now be approached through developmental genetics. Modifications of appendage number and architecture in each phylum are correlated with regulatory changes in specific patterning genes. Although their respective evolutionary histories are unique, vertebrate, insect and other animal appendages are organized by a similar genetic regulatory system that may have been established in a common ancestor.

Fossils, genes and the evolution of animal limbs

Ligands that are capable of activating Notch family receptors are broadly expressed in animal development, but their activity is tightly regulated to allow formation of tissue boundaries. Members of the fringe gene family have been implicated in limiting Notch activation during boundary formation, but the mechanism of Fringe function has not been determined. Here we present evidence that Fringe acts in the Golgi as a glycosyltransferase enzyme that modifies the epidermal growth factor (EGF) modules of Notch and alters the ability of Notch to bind its ligand Delta. Fringe catalyses the addition of N-acetylglucosamine to fucose, which is consistent with a role in the elongation of O-linked fucose O-glycosylation that is associated with EGF repeats. We suggest that cell-type-specific modification of glycosylation may provide a general mechanism to regulate ligand-receptor interactions in vivo.

Glycosyltransferase activity of Fringe modulates Notch-Delta interactions.

‘‘Fibroblast growth factor’’ (FGF) was first identified 25 years ago as a mitogenic activity in pituitary extracts (Armelin 1973; Gospodarowicz 1974). This modest observation subsequently led to the identification of a large family of proteins that affect cell proliferation, differentiation, survival, and motility (for review, see Basilico and Moscatelli 1992; Baird 1994). Recently, evidence has been accumulating that specific members of the FGF family function as key intercellular signaling molecules in embryogenesis (for review, see Goldfarb 1996). Indeed, it may be no exaggeration to say that, in conjunction with the members of a small number of other signaling molecule families [including WNT (Parr and McMahon 1994), Hedgehog (HH) (Hammerschmidt et al. 1997), and bone morphogenetic protein (BMP) (Hogan 1996)], FGFs are responsible for inducing and/or regulating the subsequent development of most organs in the vertebrate body. The purpose of this review is to discuss the functions performed by members of the FGF family in one of the best-studied vertebrate developmental systems—limb formation. It focuses initially on what is known about FGF function in the established limb bud and then discusses the mechanisms by which the signaling centers that control outgrowth and patterning of the established limb bud are formed, emphasizing possible roles played by FGFs in these processes. Finally, it discusses the potential role of FGFs in the induction of limb development. The insights into the requirement for FGF signaling in bone development that have been gained from analyses of mutations in human and mouse FGF receptor (FGFR) genes will not be discussed, as those studies have been the subject of several recent reviews (Wilkie et al. 1995; Yamaguchi and Rossant 1995; De Moerlooze and Dickson 1997; Webster and Donoghue 1997).

/pdf/the-roles-of-fgfs-in-the-early-development-of-vertebrate-fqlicfswwh.pdf

The roles of FGFs in the early development of vertebrate limbs

The apical ectodermal ridge of the vertebrate limb bud lies at the junction of the dorsal and ventral ectoderm and directs patterning of the growing limb. Its formation is directed by the boundary between cells that do and cells that do not express the gene Radical fringe. This is similar to the establishment of the margin cells at the Drosophila wing dorsoventral border by fringe. Radical fringe expression in chick-limb dorsal ectoderm is established in part through repression by Engrailed-1 in the ventral ectoderm.

Expression of Radical fringe in limb-bud ectoderm regulates apical ectodermal ridge formation

In 1996, two of us (H.Z. and L.N.) reported that expression of a dominant-negative form of BMP receptor ( dnBMPR-IB ) in the embryonic chick hindlimb inhibited interdigital apoptosis and led to webbing of the digits ([1][1]) (BMPs are signaling molecules of the transforming growth factor–β

BMP expression in duck interdigital webbing: a reanalysis.

Isolated DNA encoding a protein or polypeptide having at least one biological activity of a vertebrate fringe protein, as well as the protein or polypeptide encoded thereby, are described. Assays for identifying agents which alter the expression of the described fringe genes and assays for agents which alter the production of angiogenic precursors, the formation of the apical ectodermal ridge and the subdivisions of the neural tube are also described.

Olivia E. Orozco

Papers

Expression of Radical fringe in limb-bud ectoderm regulates apical ectodermal ridge formation

BMP expression in duck interdigital webbing: a reanalysis.

Fringe proteins and pattern formation

Vertebrate fringe proteins