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First published online December 22, 2008
doi: 10.1242/10.1242/dev.024158

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Growing models of vertebrate limb development

Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK

View larger version (43K): [in this window] [in a new window]   Fig. 1. French flag models illustrating potential roles of growth in embryonic patterning. The three colours of the French flag depict positional values that specify different cell fates across an embryonic field, such as the limb bud, over time (see Wolpert, 1969; Wolpert, 1989). (A) Progressive specification. The blue value is specified first, followed by the white and the red as growth occurs. The final positions that make up the final flag are attained by the displacement of blue, white and then red cells from the right-hand side of the field over time by growth. (B) Intercalary specification. The outlying blue and red positional values are specified first and the disparity between these extreme values promotes local growth that provides the white intermediate positional value. (C) Early specification. The coloured positional values that make up the flag are specified very early by, for example, a morphogen gradient, and further growth expands the field.

View larger version (32K): [in this window] [in a new window]   Fig. 2. Chick wing and mouse forelimb development. (A) A schematic of fully developed chick wing (yellow) and mouse forelimb (blue) skeletons with anteroposterior (AP) and proximodistal (PD) axes shown (as applied to all elements except the humerus). (B) Schematics of equivalently staged chick wing (Hamburger-Hamilton stages, HH) and mouse forelimb buds (embryonic day, E), from early stages to hand plate development. Note, mouse hindlimb development is delayed by about half a day relative to the forelimb (Martin, 1990; Fernandez-Teran et al., 2006). (C) Timeline of Shh, Fgf4 and Fgf8 expression in relation to embryonic stages shown in B (thin line indicates very low Shh expression in the chick wing). (D) (a) Orientation of AP, PD and DV axes in early stage limb buds. (b) A schematic of the expression of: Shh in the polarizing region, Fgf8 throughout the apical ectodermal ridge (AER) and Fgf4 in the posterior AER.

View larger version (32K): [in this window] [in a new window]   Fig. 3. Three models of proximodistal patterning in chick and mouse limbs. Schematics of how positional values (red, white and blue) are established that specify different proximodistal (PD) structures. (A) Apical ectodermal ridge (AER) removal in the chick wing at different stages leads to truncations, the extent of which depends on when the operation is performed (the earliest developmental stage is to the left). These results have been explained by two different models. (a) Progress zone model of chick wing PD patterning (Summerbell et al., 1973). Positional values are specified depending on the length of time cells remain in the distal progress zone (the right-hand side of the field in the figure). Cells that are displaced first from the progress zone form the humerus (blue), followed by forearm (white) and finally digits (red). AER removal terminates progress zone activity (shown by the loss of the white and red values). (b) Early specification model of chick wing PD patterning (Dudley et al., 2002). All three positional values, humerus (blue), forearm (white) and digits (red) are specified in the early chick wing bud prior to outgrowth and are expanded by growth. An alternative explanation for the limb truncations that follow AER removal is that cell death eliminates distal pre-specified positional values (crosses). Outcomes of some genetic experiments in the mouse have also supported this model (see main text for references and details). (B) Intercalation model of mouse limb PD patterning (Mariani et al., 2008). Reducing FGF activity in the AER of the mouse limb can lead to loss of intermediate structures, while distal and proximal structures still form (as shown in schematic of the skeleton), suggesting that positional values of the humerus (blue) and digits (red) are specified first in the early mouse limb bud with intermediate positional values (white) generated by intercalation. A loss of digits across the AP limb axis also occurs in these experiments.

View larger version (26K): [in this window] [in a new window]   Fig. 4. Growth-morphogen model of chick wing anteroposterior patterning. [See Towers et al. (Towers et al., 2008).] In this figure, squares represent positional values and numbers indicate which digits have been specified. Timings, shown on the vertical axis, estimate the duration of Shh activity required for the specification of digits. Left is posterior, right is anterior. (A) Normal chick wing development. Shh protein emanating from the posterior polarizing region (left-hand side) promotes sufficient AP growth of the mesenchymal field for three digits to form (digits 2, 3 and 4). Simultaneously, the Shh specification gradient forms over the field and establishes the three AP positional values of each digit identity; low levels, digit 2 (red); intermediate levels, digit 3 (white); and high levels, digit 4 (blue). Specification involves cells being promoted through increasing AP positional values and is predicted from experimental data to take 16-24 hours (Smith, 1980; Yang et al., 1997). Positional values are remembered; digit differentiation occurs later in the sequence digit 4, 3 and 2, as shown in the skeletons below. (B) Reduced Shh signalling. Cyclopamine treatment blocks Shh-dependent AP expansion of the mesenchymal field to the extent that only two digits can form, as depicted in the skeleton (Scherz et al., 2007). Simultaneously, reduced Shh signalling specifies only anterior digits 2 and 3 (red and white). (C) Reduced proliferation and growth. TSA-treatment irreversibly inhibits AP expansion of the mesenchymal field during the interval when digits are normally specified. In the most severely affected wings, only one digit can form, as depicted in the skeleton. The duration of Shh signalling is not affected, so a single posterior digit 4 (blue) is specified.

View larger version (46K): [in this window] [in a new window]   Fig. 5. Extended flag models of mouse limb anteroposterior patterning. In this figure, the squares represent positional values and numbers indicate which digits have been specified. Timings, shown on the vertical axis, estimate the duration of Shh activity required for the specification of hindlimb digits. Left is posterior, right is anterior. Digit 1 is considered to form independently of Shh signalling in the hindlimb (black). (A) Temporal expansion model (Harfe et al., 2004). Positional values of the digits 3 (dark blue) and digit 2 (white) are specified by a morphogen gradient mechanism, involving Shh, although the involvement of mesenchymal expansion is unclear. Posterior digits 4 (purple) and 5 (light blue) are specified according to the length of time cells remain in the polarizing region, which exclusively contributes to these two digits. This could require the full duration of Shh activity (60 hours) but does not require a concentration gradient of Shh protein. Digit 3 (dark blue) can be specified by a combination of the above processes, as depicted. (B) Temporal expansion model in dispatched 1 (Disp1) mutant limbs (Harfe et al., 2004). Top, schematic of mouse Disp1 mutant limb skeleton. Bottom, restricted long-range Shh movement prevents the positional value of digit 2 (white) from being established. Posterior digits are still specified by a timing mechanism linked to the proliferation of Shh-expressing polarizing region cells. (C) Biphasic model (Zhu et al., 2008). Positional identities of all five digits require less than 9 hours of Shh activity to be specified by an unknown mechanism that could involve a concentration gradient. A longer duration of Shh activity allows the survival of specified digit progenitor cells (shown by progressive enlargement of boxes representing different digits); digits differentiate in the order shown in the skeletons underneath. (D) Alternating temporal expansion/growth morphogen model. Positional values of digits 2 (white) and 3 (dark blue) are specified in the same way as digits 2-4 of the chick wing by a growth-morphogen mechanism (see Fig. 4A). At the same time, digits 4 (purple) and 5 (light blue) begin to be specified by temporal expansion (see Fig. 5A), resulting in an alternating sequence of specification that recapitulates the sequence in which digits develop with increasing lengths of exposure to Shh signalling (see Fig. 5C). (E) Alternating temporal expansion/growth morphogen model in valproate-treated limbs. Top, schematic of valproate-treated mouse limb skeleton (Faiella et al., 2000). Valproate treatment could irreversibly restrict AP expansion of the mouse limb, without affecting the timing of posterior digit specification or the Shh concentration gradient. This results in all descendant cells of the polarizing region being specified as digit 5 (light blue) and the concentration gradient of Shh establishing the positional values of digit 3 (dark blue) (compare with Fig. 4C).

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