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Proximal to Distal Patterning During Limb Development and Regeneration: a Review of Converging Disciplines

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Proximal to Distal Patterning During Limb Development and Regeneration: a Review of Converging Disciplines Review For reprint orders, please contact: [email protected] Proximal to distal patterning during limb development and regeneration: a review of converging disciplines Regeneration of lost structures typically involves distinct events: wound healing at the damaged site, the accumulation of cells that will be used as future building blocks and, finally, the initiation of molecular signaling pathways that dictate the form and pattern of the regenerated structures. Amphibians and urodeles in particular, have long been known to have exceptional regenerative properties. For many years, these animals have been the model of choice for understanding limb regeneration, a complex process that involves reconstructing skin, muscle, bone, connective tissue and nerves into a functional 3D structure. It appears that this process of rebuilding an adult limb has many similarities with how the limb forms in the first place – for example, in the embryo, all the components of the limb need to be formed and this requires signaling mechanisms to specify the final pattern. Thus, both limb formation and limb regeneration are likely to employ the same molecular pathways. Given the available tools of molecular biology and genetics, this is an exciting time for both fields to share findings and make significant progress in understanding more about the events that dictate embryonic limb pattern and control limb regeneration. This article focuses particularly on what is known about the molecular control of patterning along the proximal–distal axis. KEYWORDS: blastema digit limb development limb regeneration Francesca V Mariani proximal–distal patterning stem cell Eli & Edythe Broad Center for Regenerative Medicine & Stem Cell Research, Keck School of Medicine, Limb development & regeneration shell that, in tetrapods (but not fish), forms a University of Southern California, 1450 Biggy Street, NRT-4505, Over 250 years ago, the dedicated Italian sci- thickening at the distal tip called the apical Los Angeles, CA 90033-9601, USA entist, Lazzaro Spallanzani, first described the ectodermal ridge (AER). The AER is a site of Tel.: +1 323 442 7855 ability of urodeles (salamanders) to regenerate expression for a number of growth factors that Fax: +1 323 442 7899 [email protected] appendages [1]. Since that time, scientists have are actively being studied for their role in limb been fascinated by the idea that our organs and bud outgrowth and patterning [4,5]. As cells in appendages may have the capacity to regener- the underlying mesenchyme proliferate, the ate, and hope for a time when regeneration can bud enlarges. Next, some of the cells differen- be enhanced in the clinic. A tremendous effort tiate into chondrocytes that coalesce into con- will be required to understand regenerative densations. Interestingly, these condensations processes in such a way that patients can truly are arranged in a pattern that prefigures the benefit. Interestingly, while it is clear that there different skeletal elements. The condensations are some essential differences between limb elaborate, grow and, subsequently, differenti- regeneration and how they form during embry- ate into cartilage. The cartilage then serves as onic development, recent studies suggest that a ‘template’ for the later differentiation into both processes share a basic molecular ‘toolkit’. bone, a process called endochondral bone for- Indeed, regeneration may involve the reactiva- mation. The limb mesenchyme will differenti- tion of the developmental program to generate ate into chondrocytes and connective tissues missing structures [2,3]. Perhaps if we can learn (tendons and muscle sheath), while muscle, more about this toolkit using modern molecu- blood vessels and nerves develop from cells that lar and genetic techniques, it will be possible, migrate into the limb bud from other locations one day, to stimulate appendage regeneration in the embryo. in humans. Limb regeneration Limb development In general, vertebrates have a limited ability to The vertebrate limb typically develops dur- regenerate, with urodeles, fish and premeta- ing mid-gestation as a bud of mesenchyme morphosing frogs being the only vertebrates that protrudes from the flank of the embryo known to regenerate a complete appendage. (Figure 1A). This bud is encased in an epithelial Amphibian limb regeneration can be most 10.2217/RME.10.27 © 2010 Future Medicine Ltd Regen. Med. (2010) 5(3), 451–462 ISSN 1746-0751 451 Review Mariani Limb development Bud formation AER formation Bud outgrowth Chondrocyte Cartilage formation and patterning condensation, morphogenesis Limb regeneration Urodeles Injury Wound healing and Blastema formation Chondrocyte Cartilage formation AEC formation and growth condensation, morphogenesis Mammals Injury Wound healing Growth and Regenerated bone local proliferation Limb skeletal morphology ` l ximal ` Dista Pro Stylopod Zeugopod Autopod Figure 1. The steps of limb development and regeneration compared. (A) Limb development. (B) Limb regeneration in urodeles and digit-tip regeneration in mammals. After wound healing, the first similarity is the formation of a epithelium at the distal tip. This epithelium is called the AER during development and the AEC during regeneration. Within both the limb-bud mesenchyme and the regenerating blastema, cells proliferate, acquire positional information and respond to inductive signals. The cells differentiate and become organized to form the limb elements. During both limb development and regeneration in salamanders, cartilage prefigures the formation of bone. In mouse digit-tip regeneration, bone forms directly. (C) Final skeletal morphology of a human limb with the three limb segments color coded: stylopod (gray), zeugopod (yellow) and autopod (purple). The proximal and distal axis is indicated. AEC: Apical epithelial cap; AER: Apical ectodermal ridge. easily described as a series of defined events (out- through the process of patterning, chondrocyte lined in Figure 1B). After an injury occurs, there condensation, cartilage formation and bone is an immediate clotting response and the mobi- deposition [2,6,7]. Interestingly, the site of injury lization of the immune cells involved in wound can occur at any proximal to distal (P–D) loca- healing. Very quickly, epithelial cells cover over tion along the limb and the cells in the blastema the wound area and form a thickened structure faithfully replace the missing parts. called the apical epithelial cap (AEC), a struc- ture that is probably analogous to the AER in the What are the questions in the developing limb bud. Underneath the AEC, cells regeneration field? with an undifferentiated or mesenchymal mor- In the mid-1980s, Stocum outlined the central phology accumulate to form a structure called questions in the field of limb regeneration [6] the blastema. Like cells in the developing limb and, although some progress has been made, bud, cells in the blastema proliferate and eventu- these central questions are still unanswered and ally undergo differentiation and morphogenesis have been recast here in modern terms. 452 Regen. Med. (2010) 5(3) future science group Proximal to distal patterning during limb development & regeneration Review The first question concerns the origin of P–D patterning: three models the blastema cells. Where do these cells come to consider from? Do they originate from differentiated The Progress Zone Model skeletal, connective tissue and muscle cells in Currently, there are three models for how P–D the remaining stump? If so, do they dediffer- patterning information might be acquired and entiate to revert to a stem cell or embryonic interpreted either during limb development or state? Alternatively, are the blastema cells regeneration: the Progress Zone Model, the derived from resident stem cell populations in Early-specification Model and the Two-signal the adult stump that then move into the blas- Model (Figure 2). For many years, the Progress tema and build new structures? Related to these Zone Model, proposed by Lewis Wolpert [21], questions is the issue of whether or not cells in has been the prevailing framework for explain- the blastema are multipotent cells or are already ing how the limb develops. This model proposes restricted in potential. These are active research that a special region of defined size, called the questions [8] and the answers will be of great progress zone, exists in the distal mesenchyme. interest to the field. Wolpert and colleagues postulated that cells in The second central question, and the focus of this zone are under the influence of the AER, this article, concerns the patterning of the blas- which plays a ‘permissive’ rather than ‘instruc- tema, a structure that appears to have similari- tive’ role, meaning the AER does not impart pat- ties to the embryonic limb bud. What signals terning information to the cells but keeps the instruct the blastema cells to rebuild the missing cells ‘labile’ and able to change positional infor- parts of the limb so that the regenerated struc- mation. The cells are also proposed to be able ture has the correct patterning, morphology and to ‘mark time’ as they are within the progress polarity? Where do these signals come from? zone and become more ‘distalized’ the longer Do cells at the cut edge retain some informa- they reside in the zone. Therefore, as the limb tion that can be conveyed to the new structures bud expands, the first cells to leave the progress as they form? For convenience, the vertebrate zone are the least distalized and postulated to limb can be described as having three axes: contribute to proximal structures. Cells that an anterior–posterior axis (thumb to pinky), leave the progress zone last contribute to distal a dorsal–ventral axis (back of the hand to the structures as they have resided the longest in the palm) and a P–D axis (base of the limb to tip progress zone and are, therefore, the most distal- of the finger). The P–D axis can be further ized. Thus, the Progress Zone Model proposes divided into three different segments: a most that the P–D axis of the limb becomes specified proximal element (stylopod or upper arm/leg), a in a P–D direction through time.
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