In vertebrates, tendons connect muscles to skeletal elements. Surgical experiments in the chick have underlined developmental interactions between tendons and muscles. Initial formation of tendons occurs autonomously with respect to muscle. However, further tendon development requires the presence of muscle. The molecular signals involved in these interactions remain unknown. In the chick limb, Fgf4 transcripts are located at the extremities of muscles, where the future tendons will attach. In this paper, we analyse the putative role of muscle-Fgf4 on tendon development. We have used three general tendon markers, scleraxis, tenascin, and Fgf8 to analyse the regulation of these tendon-associated molecules by Fgf4 under different experimental conditions. In the absence of Fgf4, in muscleless and aneural limbs, the expression of the three tendon-associated molecules, scleraxis, tenascin, and Fgf8, is down-regulated. Exogenous implantation of Fgf4 in normal, aneural, and muscleless limbs induces scleraxis and tenascin expression but not that of Fgf8. These results indicate that Fgf4 expressed in muscle is required for the maintenance of scleraxis and tenascin but not Fgf8 expression in tendons.

Fgf8 exerts a strong effect on the mesenchymal cells of neural crest (NC) origin that are fated to form the facial skeleton. Surgical extirpation of facial skeletogenic NC domain (including mid-diencephalon down through rhombomere 2), which does not express Hox genes, results in the failure of facial skeleton development and inhibition of the closure of the forebrain neural tube, while Fgf8 expression in the telencephalon and in the branchial arch (BA) ectoderm is abolished. We demonstrate here that (i) exogenous FGF8 is able to rescue facial skeleton development by promoting the proliferation of NC cells from a single rhombomere, r3, which in normal development contributes only marginally to mesenchyme of BA1, and (ii) expression of Fgf8 in forebrain and in BA ectoderm is subjected to signal(s) arising from NC cells, thus showing that the development of cephalic NC-derived structures depends on FGF8 signaling, which is itself triggered by the NC cells.cephalic neural crest ͉ facial skeleton ͉ forebrain ͉ regeneration ͉ quail-chick chimeras I n vertebrates, the skeleton and connective components of the face are derived from the cephalic neural crest (NC), which can be divided into two domains. The first, a rostral domain, in which no Hox genes are expressed, extends from the presumptive level of the epiphysis down through the second rhombomere (r2); it yields the cartilages and membrane bones of the face (Fig. 1 A). It is referred to here as the facial skeletogenic NC (FSNC). The second, posterior domain (from r4 through r8) generates part of the hyoid cartilages and does not form any membrane bone. In this posterior domain of the NC, Hox genes of the four first paralogous groups are expressed both in neural tube and NC (1-3). A few NC cells (NCC) from r3 contribute to both domains. However, this contribution to branchial arches (BAs) is very small because most r3-derived NCC are undergoing apoptosis (4, 5).When the entire Hox-negative domain of the NC is removed, no facial structures develop, meaning that Hox-expressing NCC do not substitute for the Hox-negative ones (6, 7). In contrast, any fragment of the Hox-negative crest, grafted in the anterior cephalic region following the ablation of the FSNC, can regenerate a normal face (6). Thus, the Hox-negative crest behaves as an equivalence group showing that, at the early stages, the crest cells themselves do not possess the information to construct the specific bones and cartilages that constitute the facial skeleton. The ventrolateral endoderm of the foregut is able to provide the NCC with the information necessary for patterning the facial skeleton and also the hyoid cartilage (6,8). Later in development of the facial structures, the ectoderm of the facial process also participates in the final patterning of the beak (9, 10).The investigations reported here were prompted by the observation that removal of the FSNC resulted in a dramatic decrease of Fgf8 expression in the forebrain anlage, as well as in the BA ectoderm ( Fig. 1 B-E). This was followed by the t...

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