Makanae A et al. (2014), Implication of two different regeneration syste...

XB-ART-53357

Regeneration (Oxf) 2014 Aug 29;13:1-9. doi: 10.1002/reg2.16.

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Implication of two different regeneration systems in limb regeneration.

Makanae A , Mitogawa K , Satoh A .

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Limb regeneration is a representative phenomenon of organ regeneration in urodele amphibians, such as an axolotl. An amputated limb starts regenerating from a remaining stump (proximal) to lost finger tips (distal). In the present case, proximal-distal (PD) reorganization takes place in a regenerating tissue, called a blastema. It has been a mystery how an induced blastema recognizes its position and restores an exact replica of missing parts. Recently, a new experimental system called the accessory limb model (ALM) has been established. The gained ALM phenotypes are demanding to reconsider the reorganization PD positional values. Based on the ALM phenotype, it is reasonable to hypothesize that reorganization of positional values has a certain discontinuity and that two different regeneration systems cooperatively reorganize the PD axis to restore an original structure. In this review, PD axis reestablishments are focused on limb regeneration. Knowledge from ALM studies in axolotls and Xenopus is providing a novel concept of PD axis reorganization in limb regeneration.

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Species referenced: Xenopus
Genes referenced: bmp2 bmp7.1

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	Figure 1. Accessory limb formation in axolotls. (A) A typical phenotype of accessory limb induction in the stylopod. (A, insets) Accessory limb induction in the zeugopod region. Autopod part was induced. Right is the Alcian Blue staining to visualize the skeletal pattern. (B) Cartilage was visualized by Alcian Blue and calcified bone was visualized by Alizarin Red. Auto.,Â autopod; Zeug.,Â zeugopod; Styl.,Â stylopod.
	Figure 2. Proximalâdistal reorganization in the ALM. Top: Conceptual positional values. S, stylopod; Z, zeugopod; A,Â autopod. Numbers 1â10 are assigned from proximal to distal. Left column: Regeneration in an amputated limb. Stylopod is amputated at the S5 position and S6â10 are restored by a regular limb regeneration process. Middle column: Accessory limb induction in a stylopod region. Basically the limb surface (skin) is damaged and a blastema is induced on the surface of the limb. A blastema acquires A+Z values, resulting in lower limb formation. Right column: An accessory limb with half stylopod. Wounding reaches a stylopod bone and a blastema is induced on the damaged bone. The induced blastema contains S6â10 values and regenerates an accessory limb with half stylopod.
	Figure 3. Histological observation. (A), (B) Skeletal pattern was visualized by Alizarin Red and Alcian Blue. (B) Higher magnification of (A). Some ectopic bone formations can be seen in the proximal region. Such ectopic bone particles cannot be seen in the distal region. (C) Hematoxylin, eosin, and Alcian Blue staining. The regenerating half stylopod consisted of relatively fat cartilage compared with cartilage in the distal region.
	Figure 4. Blastema expresses Bmp2 and Bmp7. Bmp2 and Bmp7 expression was investigated by reverse transcription polymerase chain reaction (PCR). Efâ1a is an internal control. Samples were prepared as indicated. PCR was performed by Takara ExTaq. The number of PCR cycles is 30.
	Figure 5. An interpretation of previous experimental results. The illustration is drawn on the basis of the results reported by Goss (1956). (A) Both ulna and radius were removed and the limb was amputated at the wrist level. Because amputation was achieved at the wrist level, only autopodial elements should have been regenerated in theory. However, partial zeugopodial regeneration took place. (B) An interpretation of Goss's experiment. The ulna was extirpated and the limb was amputated. A partial ulna was regenerated. The experiment in (A) suggests that blastema cells can invade into a cavity and participate in proximal regeneration. Therefore, it is likely that blastema cells invade into a cavity and regenerate partial ulna. (C) An ulna was added to the stylopod and the limb was amputated. The added ulna was regenerated but distal parts showed a normal skeletal pattern without any duplicated skeletal elements. When a humerus was engrafted, the same phenotype was obtained (inset). The humerus was grafted as indicated in Goss (1956). The regenerated humerus was fused to the other. This fusion was also reported by Goss (1956). The regenerated distal parts were normal (n = 4/4).
	Figure 6. Xenopus limb regeneration and ectopic blastema formation. Left column: Regeneration in an amputated limb. Stylopod is amputated at the S5 position. Hypomorphic structure, called a spike, is induced. Middle column: Accessory blastema induction in a stylopod region. All nerve bundles are rerouted to the skin wound, leading to an ectopic blastema formation. However, the induced blastema cannot keep growing and shrinks at last (inset). Right column: An accessory spike formation. Wounding reaches a stylopod bone and a blastema is induced on the damaged bone. The induced blastema forms a cartilaginous spike. In the picture spike and blastema are induced in the posterior region, not the anterior region, for experimental reasons.

References [+] :

Agata, Unifying principles of regeneration I: Epimorphosis versus morphallaxis. 2007, Pubmed