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Fig. 4. Comparison of forelimb development and phenotypes derived from genetic studies in the mouse. (A) Models for AER-FGF functions in mesenchymal differentiation and chondrogenic primordia formation along the PD axis during normal limb development. Fgf8 expression in limb field ectoderm at early stages of development stimulates the FGFR-dependent MAP kinase signaling pathway in all mesenchymal cells of the nascent limb bud (red shading) (Corson et al., 2003). Initial Sox9 expression demarcates the stylopod primordia. Having received AER-FGF signals, these Sox9-expressing cells commit to osteochondroprogenitors and will form a mesenchymal condensation. Distal mesenchymal cells, which remain undifferentiated, continue to proliferate under the influence of the AER and receive AER-FGF signals. As Sox9 expression expands with limb outgrowth, the zeugopod and autopod primordia are sequentially established. (B-E) Phenotypes resulting from genetic manipulations of AER-FGF signaling. Loss of AER-FGF signaling does not prevent mesenchymal cells from expressing Sox9, but insufficient AER-FGF signaling triggers mesenchymal cell death that leads to skeletal hypoplasia. (B) Attenuated mesenchymal FGF signal transduction achieved by inactivation of Fgfr1 and Fgfr2 with the Prx1-Cre transgene (see Fig. 3). With progressive Fgfr inactivation during early limb bud development, AER-FGF signals are attenuated in limb mesenchyme. Although reduced in size, chondrogenic primordia still form along the PD axis, which leads to a normally segmented but small and dysmorphic skeleton. (C) The RAR-Cre transgene results in complete inactivation of Fgf8 before forelimb bud initiation (Moon and Capecchi, 2000). Without Fgf8, mesenchymal cells in the nascent limb bud fail to receive FGF signaling. Sox9-expressing cells that are derived from these mesenchymal cells cannot commit to osteochondroprogenitors and fail to form the stylopod primordia. Increased (and precocious) Fgf4 expression in the AER restores FGF signaling in distal undifferentiated mesenchyme allowing the zeugopod and autopod primordia to sequentially form following Sox9 expression. (D) The Msx2-Cre transgene inactivates Fgf4 and Fgf8 after forelimb bud initiation, allowing transient AER-FGF signaling (Sun et al., 2002). Initial FGF signaling in nascent limb mesenchyme ensures stylopod primordia formation. Subsequent loss of Fgf4 and Fgf8 impedes continual commitment of distal mesenchymal cells to osteochondroprogenitors, which is required for formation of normally sized skeletal segments. The severely hypoplastic zeugopod and autopod are formed from small numbers of committed mesenchymal cells that are either derived from nascent limb mesenchyme or result from partial rescue of distal limb mesenchyme by Fgf9 and Fgf17. (E) The RAR-Cre transgene results in complete inactivation of Fgf4 and Fgf8 before forelimb bud initiation (Boulet et al., 2004). Without AER-FGF signaling, Sox9-expressing cells cannot commit to osteochondroprogenitors and fail to form any chondrogenic primordia. Owing to distal mesenchymal defects, the AER or AER functions are not maintained at later stages and distal mesenchymal proliferation is inevitably reduced, which further reduces limb bud size. (F,G) Phenotypes resulting from genetic ablation of the AER at different times of limb development. Proliferation in distal mesenchyme or in mesenchyme adjacent to the AER is reduced after loss of the AER, but mesenchymal cell death is manifested only when the AER is disrupted at early stages. (F) Inactivation of Fgfr2 in the AER after forelimb bud initiation (see Figs 1, 2). AER degeneration results in an arrest of development in distal mesenchyme and autopod primordia fail to form owing to decreased mesenchymal proliferation and loss of the differentiation function of AER-FGFs. Further skeletal development of stylopod and zeugopod primordia, which are established before AER degeneration, is not affected by loss of AER functions at later developmental stages. (G) Inactivation of Fgfr2b (Revest et al., 2001) or conditional inactivation of Fgfr2 in limb field ectoderm before limb bud initiation (in the hindlimb, Figs 1, 2). The absence of any AER function results in decreased mesenchymal proliferation, massive mesenchymal cell death, and subsequent limb bud agenesis. S, stylopod; Z, zeugopod; A, autopod.

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