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First published online July 25, 2008
doi: 10.1242/10.1242/dev.021188

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Classic limb patterning models and the work of Dennis Summerbell

Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.

View larger version (28K): [in this window] [in a new window]   Fig. 1. Models of proximodistal limb patterning. (A) AER removal results in the loss of distal structures as explained by the progress zone model. According to Summerbell, AER removal serves as an assay for measuring the timing of specification of the progress zone cells. When the AER (purple) is removed at HH stage 19, the progress zone (diagonal lines) has just specified the most proximal segment, the stylopod (light blue). When it is removed at later stages, at HH21, it has specified the zeugopod (medium blue), and, at HH25, the distal autopod (dark blue). Summerbell notes that specification of the wrist elements requires a relatively long period of time spent in the progress zone (HH21-HH24) and suggests that this is due to the complexity of the structure. (B) More recently, studies have shown that the absence of distal structures following AER removal in chick is caused by cell death in the region that underlies the AER (diagonal lines) (Dudley et al., 2002). The two-signal model suggests that progenitors for proximal (light blue) and distal (dark blue) segments are specified by opposing RA and FGF signals (Capdevila et al., 1999; Mercader et al., 1999; Mercader et al., 2000; Sun et al., 2002; Mariani et al., 2008). The cell death and decreased proliferation that occurs following AER removal results in the loss of distal segments: the zeugopod and autopod at HH19, the autopod at HH21, and the distal phalanges of the autopod at HH25. The more proximal regions that have exited the progress zone remain intact, suggesting that AER removal could be used as an assay for the specification of cells just proximal to the progress zone. (C) The skeletal elements that form following AER removal at the stages indicated. AER, apical ectodermal ridge; AP, anteroposterior axis; A, autopod; FGF, fibroblast growth factor; HH, Hamburger Hamilton; PD, proximodistal axis; PZ, progress zone; RA, retinoic acid; S, stylopod; Z, zeugopod.

View larger version (30K): [in this window] [in a new window]   Fig. 2. Anteroposterior patterning in the limb bud. Our current understanding of the ZPA signal SHH. (A) Summerbell placed newspaper soaked in RA in the anterior region of an early stage limb bud. We now know that RA can induce in the forelimb the expression of genes that are not induced by SHH (green) or ZPA grafts, such as HOXB8 (Lu et al., 1997; Stratford et al., 1997). HOXB8 is sufficient to induce SHH expression in the anterior limb bud, but is not required for endogenous SHH expression (Charite et al., 1994; van den Akker et al., 1999). The application of RA to the anterior limb bud results in the induction of an anterior ZPA and mirror image duplications. In chick, the digits are labeled II-IV in the anterior to posterior direction. (B) The SHH-FGF feedback loop serves to maintain SHH signaling: SHH induces the expression of Gremlin (GRE) in non-SHH-expressing cells and GRE antagonizes BMP signaling, allowing maintained FGF signaling in the posterior AER, which then maintains SHH expression (Zuniga et al., 1999). (C) SHH signaling represses the processing of full-length GLI3 into a shorter repressor fragment (GLI3R, blue), resulting in a gradient of GLI3A (GLI3 activator) to GLI3R across the AP axis of the limb (Litingtung et al., 2002; te Welscher et al., 2002). The levels of GLI3R possibly coordinate digit identity across the AP axis. (D) The mouse limb has the digits labeled (I-V) from anterior to posterior. Based, in part, on fate mapping of SHH-descendents and SHH-responsive cells (Ahn and Joyner, 2004; Harfe et al., 2004), a model of digit patterning has emerged: digit I is SHH independent; digit II depends on SHH concentration; digit III depends on SHH concentration and the duration of SHH exposure; and digit IV and V depend on the duration of high levels of SHH signaling. AP, anteroposterior axis; BMP, bone morphogenic protein; FGF, fibroblast growth factor; PD, proximodistal axis; RA, retinoic acid; SHH, sonic hedgehog.

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