Limb development

Last updated
Development of the limbs
6 weeks pregnant.png
Illustration of a human embryo at six weeks gestational age
9-Week Human Embryo from Ectopic Pregnancy.jpg
9-week human fetus from ectopic pregnancy
Anatomical terminology

Limb development in vertebrates is an area of active research in both developmental and evolutionary biology, with much of the latter work focused on the transition from fin to limb. [1]

Contents

Limb formation begins in the morphogenetic limb field, as mesenchymal cells from the lateral plate mesoderm proliferate to the point that they cause the ectoderm above to bulge out, forming a limb bud. Fibroblast growth factor (FGF) induces the formation of an organizer at the end of the limb bud, called the apical ectodermal ridge (AER), which guides further development and controls cell death. Programmed cell death is necessary to eliminate webbing between digits.

The limb field is a region specified by expression of certain Hox genes, a subset of homeotic genes, and T-box transcription factors – Tbx5 for forelimb or wing development, and Tbx4 for leg or hindlimb development. Establishment of the forelimb field (but not hindlimb field) requires retinoic acid signaling in the developing trunk of the embryo from which the limb buds emerge. [2] [3] Also, although excess retinoic acid can alter limb patterning by ectopically activating Shh or Meis1/Meis2 expression, genetic studies in mouse that eliminate retinoic acid synthesis have shown that RA is not required for limb patterning. [4]

The limb bud remains active throughout much of limb development as it stimulates the creation and positive feedback retention of two signaling regions: the AER and its subsequent creation of the zone of polarizing activity (ZPA) with the mesenchymal cells. [5] In addition to the dorsal-ventral axis created by the ectodermal expression of competitive Wnt7a and BMP signals respectively, these AER and ZPA signaling centers are crucial to the proper formation of a limb that is correctly oriented with its corresponding axial polarity in the developing organism. [6] [7] Because these signaling systems reciprocally sustain each other's activity, limb development is essentially autonomous after these signaling regions have been established. [5]

Limb formation

Limb bud

Limb formation begins in the morphogenetic limb field. Limb formation results from a series of reciprocal tissue interactions between the mesenchyme of the lateral plate mesoderm and the overlying ectodermally derived epithelial cells. Cells from the lateral plate mesoderm and the myotome migrate to the limb field and proliferate to the point that they cause the ectoderm above to bulge out, forming the limb bud. The lateral plate cells produce the cartilaginous and skeletal portions of the limb while the myotome cells produce the muscle components.

The lateral plate mesodermal cells secrete fibroblast growth factors (FGF7 and FGF10) to induce the overlying ectoderm to form an organizer at the end of the limb bud, called the apical ectodermal ridge (AER), which guides further development and controls cell death. [8] The AER secretes further growth factors FGF8 and FGF4 which maintain the FGF10 signal and induce proliferation in the mesoderm.[ citation needed ] The position of FGF10 expression is regulated by two Wnt signaling pathways: Wnt8c in the hindlimb and Wnt2b in the forelimb. The forelimb and the hindlimb are specified by their position along the anterior/posterior axis and possibly by two transcription factors: Tbx5 and Tbx4, respectively. [9] [10]

Precartilage condensations

The limb's skeletal elements are prefigured by tight aggregates known as cellular condensations of the pre-cartilage mesenchymal cells. [11] Mesenchymal condensation is mediated by extracellular matrix and cell adhesion molecules. [12] In the process of chondrogenesis, chondrocytes differentiate from the condensations to form cartilage, giving rise to the skeletal primordia. In the development of most vertebrate limbs (though not in some amphibians), the cartilage skeleton is replaced by bone later in development.

Periodicities of the limb pattern

Vertebrate limbs are organized into stylopod, zeugopod, and autopod. Stylopod-zygopod-autopod.png
Vertebrate limbs are organized into stylopod, zeugopod, and autopod.

The limb is organized into three regions: stylopod, zeugopod, and autopod (in order from proximal to distal). The zeugopod and the autopod contain a number of periodic and quasi-periodic pattern motifs. The zeugopod consists of two parallel elements along the anteroposterior axis and the autopod contains 3-5 (in most cases) elements along the same axis. The digits also have a quasi-periodic arrangement along the proximodistal axis, consisting of tandem chains of skeletal elements. The generation of the basic limb plan during development results from the patterning of the mesenchyme by an interplay of factors that promote precartilage condensation and factors that inhibit it. [13]

The development of the basic limb plan is accompanied by the generation of local differences between the elements. For example, the radius and ulna of the forelimb, and the tibia and fibula of the hindlimb of the zeugopod are distinct from one another, as are the different fingers or toes in the autopod. These differences can be treated schematically by considering how they are reflected in each of the limb's three main axes.

A general consensus is that the patterning of the limb skeleton involves one or more Turing-type reaction–diffusion mechanisms. [1]

Evolution and development

The evolution of limbs from paired fins has been an area of much focus. [1] There have been many studies aimed at elucidating specific genes and transcription factors that are found responsible for limb development (See Table 1 below). In particular, studies have shown that SHH, DACH1, and the BMP, HOX, T-box, FGF, and WNT gene families all play a critical role in successful limb development and formation. [14] [15] In order to study the genes involved in limb development (and thus evolution) limb reduction and limb loss in snakes is a complementary approach. [16] Conserved sequences involved in limb development are retained in the genomes of snakes. Certain limb-enhancer sequences are also conserved between different types of appendage, such as limbs the phallus. [16] [17] For instance, limb-development signalling plays a role both in the development of the limbs and of the genital tubercle in mice. [16] [17] The study of limb reduction and limb loss is unravelling the genetic pathways that control limb development. [16] The Turing system has enabled a number of possible outcomes in the evolutionary steps of patterning networks. [1]

Table 1: Various genes known to be responsible for limb development (separated by gene family)
Bmp2, Bmp4, Bmp7
Dach1
En1
Fgf4, Fgf8, Fgf9, Fgf10, Fgf17, Fgfr1
Gli3
Gremlin1
Hand2
Hoxa13, Hoxd13
Msx1, Msx2
Pitx1
Shh
Tbx4, Tbx5
Wnt3, Wnt5a

Many of the genes listed in Table 1 play an important role in embryonic development, specifically during skeletal patterning and limb bud formation. [18] The Shh gene, and genes belonging to the BMP, Hox, T-box, FGF, and Wnt families, all play a pivotal role in cell signaling and differentiation to regulate and promote successful limb formation. Various other genes listed above, one example being Dach1, are DNA-binding proteins that regulate gene expression. The intricate combination of gene expression, regulation, activation, and de-activation allows these genes to produce limbs during embryonic development. Interestingly, many of these genes remain present even in animals that do not have limbs, such as snakes.

Snake evolution and limb loss

Depiction of the spatiotemporal regulation of the Shh gene in coordinating vertebrate digits (fingers) Limb bud.svg
Depiction of the spatiotemporal regulation of the Shh gene in coordinating vertebrate digits (fingers)

An interesting aspect in understanding limb development is addressing the question of how snakes lost their legs. Snakes are a particularly good example for studying limb loss, as they underwent limb loss and regeneration multiple times throughout their evolution before they finally lost their legs for good. Much of the gene expression during embryonic development is regulated via spatiotemporal and chemotactic signaling, [20] as depicted by the image to the right. Recent evidence suggests that the highly conserved genes responsible for limb development (Table 1) still remain present in limbless vertebrates, [21] indicating that during embryonic development, the production of limbs, or lack thereof, may best be explained by gene regulation.

Possible role of Shh enhancer in snake limb loss

One theory suggests that the degradation of enhancer sequences may have contributed to the progressive limb loss in snake evolution. In particular, many studies have focused on the ZPA Regulatory Sequence (ZRS) - the enhancer of the Sonic Hedgehog gene (Shh). This long-range enhancer is required for proper limb formation in several vertebrate species, with mutations in this sequence known to cause limb deformities. [17] As such, this sequence is highly conserved across a variety of vertebrate species.

Changes in the Shh enhancer ZRS (~800bp) throughout snake evolution contributed to progressive loss of enhancer function and thus limb development. ZRS Degredation Image.png
Changes in the Shh enhancer ZRS (~800bp) throughout snake evolution contributed to progressive loss of enhancer function and thus limb development.

Comparisons of the core ZRS in several snake species to the mouse and lizard sequences shows the presence of snake-specific alterations. [23] The core ZRS proved to be mainly conserved in basal snakes like the boa constrictor and python, which still contain pelvic girdle bones. [22] In contrast, advanced snakes such as the viper and cobra, in which no skeletal limb structures remain, have a much higher rate of nucleotide changes when compared to the mouse and lizard ZRS. [22] It is thought that these cumulative changes in the snake ZRS are indicative of a progressive loss of function in this enhancer throughout snake evolution. [22]

Alignment of partial ZPA Regulatory Sequence (ZRS) in vertebrates show increased substitutions in advanced snakes compared to limbed vertebrates and earlier basal snakes. Genomes from the UCSC Genome Browser and GigaDB, and orthologous ZRS enhancer sequences were compared by BLAST. After Kvon et al. ZRS alignment figure.png
Alignment of partial ZPA Regulatory Sequence (ZRS) in vertebrates show increased substitutions in advanced snakes compared to limbed vertebrates and earlier basal snakes. Genomes from the UCSC Genome Browser and GigaDB, and orthologous ZRS enhancer sequences were compared by BLAST. After Kvon et al.

Further investigation into these changes showed an increased rate of substitution in binding sites for transcription factors such as ETS1, whose binding to ZRS has been shown to activate Shh transcription. [24] This degradation in ZRS suggests that this enhancer may be important in further exploring the molecular mechanisms that propelled the morphological evolution of snakes.

Current conclusions and limitations

Snakes are not a common model organism, i.e. they are not easily genetically tractable. In addition, their genome sequence data is incomplete and suffers from poor annotation and quality. These factors make it difficult to understand the mechanism of snake limb loss using a genetic approach, targeting and observing the presence and activity of these genes and their regulatory enhancers. Many of the genes necessary for limb formation are still retained in snakes, hence limb loss can probably not be explained by gene loss.[ citation needed ]

The developing limb has to align itself in relation to three axes of symmetry. [25] These are the craniocaudal (head to tail), dorsoventral (back to front), and proximodistal (near to far) axes. [25]

Many investigations into the development of the limb skeletal pattern have been influenced by the positional information concept proposed by Lewis Wolpert in 1971. [26] In tune with this idea, efforts have been made to identify diffusive signaling molecules (morphogens) that traverse orthogonal axes of developing limbs and determine locations and identities of skeletal elements in a concentration-dependent fashion.

Proximodistal patterning

Hox genes contribute to the specification of the stylopod, zeugopod and autopod. Mutations in Hox genes lead to proximodistal losses or abnormalities. [27] Three different models have been advanced for explaining the patterning of these regions.

Progress zone model

The apical ectodermal ridge (AER) creates and maintains a zone of cell proliferation known as the progress zone. [28] It is thought that cells here gain the positional information they need to travel to their destined position. [28] It was proposed that their positional value was determined by the length of time that the cells were in the progress zone but this has yet to be proved (as of 2001). [28] Proximal structures were proposed to be formed by the first cells to leave the zone and distal ones, by cells that left later. [28]

The Progress Zone model was proposed 30 years ago but recent evidence has conflicted with this model. [29]

Experimental evidence:

  • Removing the AER at a later period of development results in less disruption of distal structures than if the AER was removed early in development.
  • Grafting an early limb bud tip onto a late wing results in duplication of structures, while grafting a late wing bud tip onto an early limb results in a deletion of structures.

Early allocation and progenitor expansion model (or prespecification model)

Cells are specified for each segment in the early limb bud and this population of cells expand out as the limb bud grows. This model is consistent with the following observations. Cell division is seen throughout the limb bud. Cell death occurs within a 200 μm zone subjacent to the AER when it is removed; cell death forecloses some patterning. FGF-releasing beads are able to rescue limb development when the AER is removed by preventing this cell death.

Experimental evidence:

  • Labeled cells in different position of an early limb bud were restricted to single segments of the limb. [30]
  • Limbs lacking expression of required FGF4 & FGF8 showed all structures of the limb and not just the proximal parts. [31]

More recently, however, the investigators primarily responsible for both the Progress Zone and Prespecification models have acknowledged that neither of these models accounts adequately for the available experimental data. [29]

Turing-type reaction–diffusion model

The Turing reaction-diffusion mechanism illustrates the complex chemical interactions involved in developmental pattern formation. "A" activates itself and "B", while "B" inhibits "A". The model depicts a slowly diffusing activator's (A) interaction with a rapidly diffusing inhibitor (B). The reaction-diffusion system is responsible for the characteristic patterning of the autopod, zeugopod, and stylopod in limb development. Turing diffusion model.jpg
The Turing reaction-diffusion mechanism illustrates the complex chemical interactions involved in developmental pattern formation. "A" activates itself and "B", while "B" inhibits "A". The model depicts a slowly diffusing activator's (A) interaction with a rapidly diffusing inhibitor (B). The reaction-diffusion system is responsible for the characteristic patterning of the autopod, zeugopod, and stylopod in limb development.

This model, a reaction–diffusion model first proposed in 1979, [33] is based on the self-organizing properties of excitable media described by Alan Turing in 1952. [34] The excitable medium is the limb bud mesenchyme, in which cells interact by positively autoregulatory morphogens such as transforming growth factor beta (TGF-β) and inhibitory signaling pathways involving fibroblast growth factor (FGF) and Notch. Proximodistal and craniocaudal axes are not considered to be independently specified, but instead emerge by transitions in the number of parallel elements as the undifferentiated apical zone of the growing limb bud undergoes reshaping. [35] This model only specifies a "bare bones" pattern. Other factors like sonic hedgehog (Shh) and Hox proteins, primary informational molecules in the other models, are proposed instead to play a fine-tuning role.

Experimental evidence:

  • Limb mesenchymal cells, when dissociated and grown in culture or reintroduced within ectodermal "hulls" can recapitulate essential aspects of pattern formation, morphogenesis and differentiation. [36] [37]
  • Peculiarities of the limb skeletal pattern in the mouse Doublefoot mutant are predicted outcomes of a Turing-type mechanism. [38]
  • Progressive reduction in distal Hox genes in a Gli3-null background results in progressively more severe polydactyly, displaying thinner and densely packed digits, suggesting (with the aid of computer modeling) that the dose of distal Hox genes modulates the period or wavelength of digits specified by a Turing-type mechanism. [39]

Craniocaudal patterning

Early signals that define the craniocaudal (anterior-posterior), and proximodistal axes in vertebrate limb development. Limb bud early signals.png
Early signals that define the craniocaudal (anterior-posterior), and proximodistal axes in vertebrate limb development.

In 1957, the discovery of the zone of polarizing activity (ZPA) in the limb bud provided a model for understanding the patterning activity by the action of a morphogenic gradient of sonic hedgehog (Shh). [40] Shh is recognised as a limb-specific enhancer. [41] Shh is both sufficient and necessary to create the ZPA and specify the craniocaudal pattern in the distal limb (Shh is not necessary for the polarity of the stylopod). Shh is turned on in the posterior through the early expression of Hoxd genes, the expression of Hoxb8, and the expression dHAND. Shh is maintained in the posterior through a feedback loop between the ZPA and the AER. Shh induces the AER to produce FGF4 and FGF8 which maintains the expression of Shh.

Digits 3,4 and 5 are specified by a temporal gradient of Shh. Digit 2 is specified by a long-range diffusible form of Shh and Digit 1 does not require Shh. Shh cleaves the Ci/Gli3 transcriptional repressor complex to convert the transcription factor Gli3 to an activator which activates the transcription of HoxD genes along the craniocaudal. Loss of the Gli3 repressor leads to the formation of generic (non-individualized) digits in extra quantities. [42]

Dorsoventral patterning

Dorsoventral patterning is mediated by Wnt7a signals in the overlying ectoderm not the mesoderm. Wnt7a is both necessary and sufficient to dorsalize the limb. Wnt7a also influences the craniocaudal and loss of Wnt7a causes the dorsal side of limbs to become ventral sides and causes missing posterior digits. Replacing Wnt7a signals rescues this defect. Wnt7a is also required to maintain expression of Shh.

Wnt7a also causes Lmx1b, a LIM Homeobox gene (and thus a transcription factor), to be expressed. Lmx1b is involved in dorsalization of the limb, which was shown by knocking out the Lmx1b gene in mice. [43] The mice lacking the Lmx1b produced ventral skin on both sides of their paws. There are other factors thought to control the DV patterning; Engrailed-1 represses the dorsalizing effect of Wnt7a on the ventral side of the limbs. [44]

See also

Related Research Articles

<span class="mw-page-title-main">Sonic hedgehog protein</span> Signaling molecule in animals

Sonic hedgehog protein (SHH) is encoded for by the SHH gene. The protein is named after the video game character Sonic the Hedgehog.

<span class="mw-page-title-main">Somitogenesis</span>

Somitogenesis is the process by which somites form. Somites are bilaterally paired blocks of paraxial mesoderm that form along the anterior-posterior axis of the developing embryo in segmented animals. In vertebrates, somites give rise to skeletal muscle, cartilage, tendons, endothelium, and dermis.

<span class="mw-page-title-main">Polydactyl cat</span> Cats with genetic anomaly that causes extra toes

A polydactyl cat is a cat with a congenital physical anomaly called polydactyly, which causes the cat to be born with more than the usual number of toes on one or more of its paws. Cats with this genetically inherited trait are most commonly found along the East Coast of North America and in South West England and Wales.

<span class="mw-page-title-main">Apical ectodermal ridge</span>

The apical ectodermal ridge (AER) is a structure that forms from the ectodermal cells at the distal end of each limb bud and acts as a major signaling center to ensure proper development of a limb. After the limb bud induces AER formation, the AER and limb mesenchyme—including the zone of polarizing activity (ZPA)—continue to communicate with each other to direct further limb development.

The limb bud is a structure formed early in vertebrate limb development. As a result of interactions between the ectoderm and underlying mesoderm, formation occurs roughly around the fourth week of development. In the development of the human embryo the upper limb bud appears in the third week and the lower limb bud appears four days later.

Gremlin is an inhibitor in the TGF beta signaling pathway. It primarily inhibits bone morphogenesis and is implicated in disorders of increased bone formation and several cancers.

<span class="mw-page-title-main">T-box</span> Genes that affect limb and heart development

T-box refers to a group of transcription factors involved in embryonic limb and heart development. Every T-box protein has a relatively large DNA-binding domain, generally comprising about a third of the entire protein that is both necessary and sufficient for sequence-specific DNA binding. All members of the T-box gene family bind to the "T-box", a DNA consensus sequence of TCACACCT.

<span class="mw-page-title-main">FGF10</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor 10 is a protein that in humans is encoded by the FGF10 gene.

<i>TBX5</i> (gene) Protein-coding gene that affects limb development and heart and bone function

T-box transcription factor TBX5, is a protein that in humans is encoded by the TBX5 gene. Abnormalities in the TBX5 gene can result in altered limb development, Holt-Oram syndrome, Tetra-amelia syndrome, and cardiac and skeletal problems.

<span class="mw-page-title-main">Fibroblast growth factor 8</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor 8(FGF-8) is a protein that in humans is encoded by the FGF8 gene.

<span class="mw-page-title-main">FGF4</span> Fibroblast growth factor gene

Fibroblast growth factor 4 is a protein that in humans is encoded by the FGF4 gene.

<span class="mw-page-title-main">TBX2</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor 2 Tbx2 is a transcription factor that is encoded by the Tbx2 gene on chromosome 17q21-22 in humans. This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. Tbx2 and Tbx3 are the only T-box transcription factors that act as transcriptional repressors rather than transcriptional activators, and are closely related in terms of development and tumorigenesis. This gene plays a significant role in embryonic and fetal development through control of gene expression, and also has implications in various cancers. Tbx2 is associated with numerous signaling pathways, BMP, TGFβ, Wnt, and FGF, which allow for patterning and proliferation during organogenesis in fetal development.

Cheryll Anne Tickle is a British scientist, known for her work in developmental biology and specifically for her research into the process by which vertebrate limbs develop ab ovo. She is an emeritus professor at the University of Bath.

<span class="mw-page-title-main">Zone of polarizing activity</span>

The zone of polarizing activity (ZPA) is an area of mesenchyme that contains signals which instruct the developing limb bud to form along the anterior/posterior axis. Limb bud is undifferentiated mesenchyme enclosed by an ectoderm covering. Eventually, the limb bud develops into bones, tendons, muscles and joints. Limb bud development relies not only on the ZPA, but also many different genes, signals, and a unique region of ectoderm called the apical ectodermal ridge (AER). Research by Saunders and Gasseling in 1948 identified the AER and its subsequent involvement in proximal distal outgrowth. Twenty years later, the same group did transplantation studies in chick limb bud and identified the ZPA. It wasn't until 1993 that Todt and Fallon showed that the AER and ZPA are dependent on each other.

Diplopodia is a congenital anomaly in tetrapods that involves duplication of elements of the foot on the hind limb. It comes from the Greek roots diplo = "double" and pod = "foot". Diplopodia is often found in conjunction with other structural abnormalities and can be lethal. It is more extreme than polydactyly, the presence of extra digits.

<span class="mw-page-title-main">Bat wing development</span>

The order Chiroptera, comprising all bats, has evolved the unique mammalian adaptation of flight. Bat wings are modified tetrapod forelimbs. Because bats are mammals, the skeletal structures in their wings are morphologically homologous to the skeletal components found in other tetrapod forelimbs. Through adaptive evolution these structures in bats have undergone many morphological changes, such as webbed digits, elongation of the forelimb, and reduction in bone thickness. Recently, there have been comparative studies of mouse and bat forelimb development to understand the genetic basis of morphological evolution. Consequently, the bat wing is a valuable evo-devo model for studying the evolution of vertebrate limb diversity.

Within molecular and cell biology, temporal feedback, also referred to as interlinked or interlocked feedback, is a biological regulatory motif in which fast and slow positive feedback loops are interlinked to create "all or none" switches. This interlinking produces separate, adjustable activation and de-activation times. This type of feedback is thought to be important in cellular processes in which an "all or none" decision is a necessary response to a specific input. The mitotic trigger, polarization in budding yeast, mammalian calcium signal transduction, EGF receptor signaling, platelet activation, and Xenopus oocyte maturation are examples for interlinked fast and slow multiple positive feedback systems.

<span class="mw-page-title-main">Hox genes in amphibians and reptiles</span>

Hox genes play a massive role in some amphibians and reptiles in their ability to regenerate lost limbs, especially HoxA and HoxD genes.

T-box transcription factor Tbx4 is a transcription factor that belongs to T-box gene family that is involved in the regulation of embryonic developmental processes. The transcription factor is encoded by the TBX4 gene located on human chromosome 17. Tbx4 is known mostly for its role in the development of the hindlimb, but it also plays a critical role in the formation of the umbilicus. Tbx4 has been shown to be expressed in the allantois, hindlimb, lung and proctodeum.

John W. Saunders Jr. was an American scientist whose research in the field of developmental biology and zoology played an integral part in helping to understand how various vertebrate limbs develop. Saunders researched the vertebrate limb and studied the apical ectodermal ridge (AER). This research was critical in recognizing growth factors that are secreted from the AER and are important in assisting the pattern of developing vertebrate limbs.

References

  1. 1 2 3 4 Stewart, TA; Bhat, R; Newman, SA (2017). "The evolutionary origin of digit patterning". EvoDevo. 8: 21. doi: 10.1186/s13227-017-0084-8 . PMC   5697439 . PMID   29201343.
  2. ↑ Stratford T, Horton C, Maden M (1996). "Retinoic acid is required for the initiation of outgrowth in the chick limb bud". Curr Biol. 6 (9): 1124–33. doi: 10.1016/S0960-9822(02)70679-9 . PMID   8805369. S2CID   14662908.
  3. ↑ Zhao X, Sirbu IO, Mic FA, et al. (June 2009). "Retinoic acid promotes limb induction through effects on body axis extension but is unnecessary for limb patterning". Curr. Biol. 19 (12): 1050–7. doi:10.1016/j.cub.2009.04.059. PMC   2701469 . PMID   19464179.
  4. ↑ Cunningham, T.J.; Duester, G. (2015). "Mechanisms of retinoic acid signalling and its roles in organ and limb development". Nat. Rev. Mol. Cell Biol. 16 (2): 110–123. doi:10.1038/nrm3932. PMC   4636111 . PMID   25560970.
  5. 1 2 Tickle, C (October 2015). "How the embryo makes a limb: determination, polarity and identity". Journal of Anatomy. 227 (4): 418–30. doi:10.1111/joa.12361. PMC   4580101 . PMID   26249743.
  6. ↑ Parr, BA; McMahon, AP (23 March 1995). "Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb". Nature. 374 (6520): 350–3. Bibcode:1995Natur.374..350P. doi:10.1038/374350a0. PMID   7885472. S2CID   4254409.
  7. ↑ Pizette, S; Abate-Shen, C; Niswander, L (November 2001). "BMP controls proximodistal outgrowth, via induction of the apical ectodermal ridge, and dorsoventral patterning in the vertebrate limb". Development. 128 (22): 4463–74. doi:10.1242/dev.128.22.4463. PMID   11714672.
  8. ↑ Yonei-Tamura S, Endo T, Yajima H, Ohuchi H, Ide H, Tamura K (1999). "FGF7 and FGF10 directly induce the apical ectodermal ridge in chick embryos". Dev. Biol. 211 (1): 133–43. doi: 10.1006/dbio.1999.9290 . PMID   10373311.
  9. ↑ Ohuchi H, Takeuchi J, Yoshioka H, Ishimaru Y, Ogura K, Takahashi N, Ogura T, Noji S (1998). "Correlation of wing-leg identity in ectopic FGF-induced chimeric limbs with the differential expression of chick Tbx5 and Tbx4". Development. 125 (1): 51–60. doi:10.1242/dev.125.1.51. PMID   9389663.
  10. ↑ Rodriguez-Esteban C, Tsukui T, Yonei S, Magallon J, Tamura K, Izpisua Belmonte JC (1999). "The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity". Nature. 398 (6730): 814–8. Bibcode:1999Natur.398..814R. doi:10.1038/19769. PMID   10235264. S2CID   4330287.
  11. ↑ DeLise, AM; Fischer, L; Tuan, RS (September 2000). "Cellular interactions and signaling in cartilage development". Osteoarthritis and Cartilage. 8 (5): 309–34. doi: 10.1053/joca.1999.0306 . PMID   10966838.
  12. ↑ Hall BK, Miyake T (2000). "All for one and one for all: condensations and the initiation of skeletal development". BioEssays. 22 (2): 138–47. doi:10.1002/(SICI)1521-1878(200002)22:2<138::AID-BIES5>3.0.CO;2-4. PMID   10655033.
  13. ↑ Newman SA, Bhat R (2007). "Activator-inhibitor dynamics of vertebrate limb pattern formation". Birth Defects Research Part C: Embryo Today: Reviews. 81 (4): 305–19. CiteSeerX   10.1.1.128.3260 . doi:10.1002/bdrc.20112. PMID   18228262.
  14. ↑ Leal, Francisca; Cohn, Martin J. (2016-11-07). "Loss and Re-emergence of Legs in Snakes by Modular Evolution of Sonic hedgehog and HOXD Enhancers". Current Biology. 26 (21): 2966–2973. doi: 10.1016/j.cub.2016.09.020 . ISSN   0960-9822. PMID   27773569. S2CID   4495482.
  15. ↑ Cohn, Martin J. (2008-10-07), Cardew, Gail; Goode, Jamie A. (eds.), "Developmental Mechanisms of Vertebrate Limb Evolution", Novartis Foundation Symposium, Novartis Foundation Symposia, 232, Chichester, UK: John Wiley & Sons, Ltd: 47–62, doi:10.1002/0470846658.ch5, ISBN   978-0-471-49433-1, PMID   11277086
  16. 1 2 3 4 Infante, CR; Rasys, AM; Menke, DB (January 2018). "Appendages and gene regulatory networks: Lessons from the limbless". Genesis. 56 (1): e23078. doi:10.1002/dvg.23078. PMC   5783778 . PMID   29076617.
  17. 1 2 3 Leal F, Cohn MJ (2016). "Loss and Re-emergence of Legs in Snakes by Modular Evolution of Sonic hedgehog and HOXD Enhancers". Curr Biol. 26 (21): 2966–2973. doi: 10.1016/j.cub.2016.09.020 . PMID   27773569. S2CID   4495482.
  18. ↑ Tickle, Cheryll; Towers, Matthew (2017). "Sonic Hedgehog Signaling in Limb Development". Frontiers in Cell and Developmental Biology. 5: 14. doi: 10.3389/fcell.2017.00014 . ISSN   2296-634X. PMC   5328949 . PMID   28293554.
  19. ↑ Harfe, Brian D.; Scherz, Paul J.; Nissim, Sahar; Tian, Hua; McMahon, Andrew P.; Tabin, Clifford J. (2004-08-20). "Evidence for an Expansion-Based Temporal Shh Gradient in Specifying Vertebrate Digit Identities". Cell. 118 (4): 517–528. doi: 10.1016/j.cell.2004.07.024 . ISSN   0092-8674. PMID   15315763. S2CID   16280983.
  20. ↑ Harfe, Brian D.; Scherz, Paul J.; Nissim, Sahar; Tian, Hua; McMahon, Andrew P.; Tabin, Clifford J. (2004-08-20). "Evidence for an Expansion-Based Temporal Shh Gradient in Specifying Vertebrate Digit Identities". Cell. 118 (4): 517–528. doi: 10.1016/j.cell.2004.07.024 . ISSN   0092-8674. PMID   15315763. S2CID   16280983.
  21. ↑ Kvon, Evgeny Z.; Kamneva, Olga K.; Melo, Uirá S.; Barozzi, Iros; Osterwalder, Marco; Mannion, Brandon J.; Tissières, Virginie; Pickle, Catherine S.; Plajzer-Frick, Ingrid; Lee, Elizabeth A.; Kato, Momoe (2016-10-20). "Progressive Loss of Function in a Limb Enhancer during Snake Evolution". Cell. 167 (3): 633–642.e11. doi:10.1016/j.cell.2016.09.028. ISSN   0092-8674. PMC   5484524 . PMID   27768887.
  22. 1 2 3 4 5 Kvon EZ, Kamneva OK, Melo US, Barozzi I, Osterwalder M, Mannion BJ, et al. (2016). "Progressive Loss of Function in a Limb Enhancer during Snake Evolution". Cell. 167 (3): 633–642.e11. doi:10.1016/j.cell.2016.09.028. PMC   5484524 . PMID   27768887.
  23. ↑ Burgess DJ (2016). "Development: Sonic snakes and regulation of limb formation". Nat Rev Genet. 17 (12): 715. doi: 10.1038/nrg.2016.149 . PMID   27843141. S2CID   28930888.
  24. ↑ Xu C, Yang X, Zhou H, Li Y, Xing C, Zhou T, et al. (2020). "A novel ZRS variant causes preaxial polydactyly type I by increased sonic hedgehog expression in the developing limb bud". Genet Med. 22 (1): 189–198. doi:10.1038/s41436-019-0626-7. PMC   6944640 . PMID   31395945.
  25. 1 2 Larsen, William (2001). Human embryology (3rd ed.). Philadelphia, Pa.: Churchill Livingstone. p. 335. ISBN   978-0-443-06583-5.
  26. ↑ Wolpert L (1971). Positional information and pattern formation. Current Topics in Developmental Biology. Vol. 6. pp. 183–224. doi:10.1016/S0070-2153(08)60641-9. ISBN   9780121531065. PMID   4950136.{{cite book}}: |journal= ignored (help)
  27. ↑ Wellik D, Capecchi M (2003). "Hox10 and Hox11 genes are required to globally pattern the mammalian skeleton". Science. 301 (5631): 363–7. Bibcode:2003Sci...301..363W. doi:10.1126/science.1085672. PMID   12869760. S2CID   9751891.
  28. 1 2 3 4 Larsen, William (2001). Human embryology (3rd ed.). Philadelphia, Pa.: Churchill Livingstone. p. 337. ISBN   978-0-443-06583-5.
  29. 1 2 Tabin C, Wolpert L (2007). "Rethinking the proximodistal axis of the vertebrate limb in the molecular era". Genes Dev. 21 (12): 1433–42. doi: 10.1101/gad.1547407 . PMID   17575045.
  30. ↑ Dudley A, Ros M, Tabin C (2002). "A re-examination of proximodistal patterning during vertebrate limb development". Nature. 418 (6897): 539–44. Bibcode:2002Natur.418..539D. doi:10.1038/nature00945. PMID   12152081. S2CID   1357061.
  31. ↑ Sun X, Mariani F, Martin G (2002). "Functions of FGF signalling from the apical ectodermal ridge in limb development". Nature. 418 (6897): 501–8. Bibcode:2002Natur.418..501S. doi:10.1038/nature00902. PMID   12152071. S2CID   4409248.
  32. ↑ Gilbert, S. F.; Barresi, M. J. F. (May 2017). "Developmental Biology". American Journal of Medical Genetics Part A. 173 (5) (11th EDITION ed.): 1430–1430. doi:10.1002/ajmg.a.38166. ISSN   1552-4825.
  33. ↑ Newman SA, Frisch HL (1979). "Dynamics of skeletal pattern formation in developing chick limb". Science. 205 (4407): 662–668. Bibcode:1979Sci...205..662N. doi:10.1126/science.462174. PMID   462174. S2CID   44653825.
  34. ↑ Turing, AM (1952). "The Chemical Basis of Morphogenesis". Philosophical Transactions of the Royal Society B . 237 (641): 37–72. Bibcode:1952RSPTB.237...37T. doi: 10.1098/rstb.1952.0012 .
  35. ↑ Zhu J, Zhang YT, Alber MS, Newman SA (2010). "Bare bones pattern formation: a core regulatory network in varying geometries reproduces major features of vertebrate limb development and evolution". PLOS ONE. 5 (5): e:10892. Bibcode:2010PLoSO...510892Z. doi: 10.1371/journal.pone.0010892 . PMC   2878345 . PMID   20531940.
  36. ↑ Moftah MZ, Downie SA, Bronstein NB, Mezentseva N, Pu J, Maher PA, Newman SA (2002). "Ectodermal FGFs induce perinodular inhibition of limb chondrogenesis in vitro and in vivo via FGF receptor 2". Dev. Biol. 249 (2): 270–82. doi: 10.1006/dbio.2002.0766 . PMID   12221006.
  37. ↑ Ros MA, Lyons GE, Mackem S, Fallon JF (1994). "Recombinant limbs as a model to study homeobox gene regulation during limb development". Dev. Biol. 166 (1): 59–72. doi:10.1006/dbio.1994.1296. PMID   7958460.
  38. ↑ Miura T, Shiota K, Morriss-Kay G, Maini PK (2006). "Mixed-mode pattern in Doublefoot mutant mouse limb−Turing reaction-diffusion model on a growing domain during limb development". J Theor Biol . 240 (4): 562–73. Bibcode:2006JThBi.240..562M. doi:10.1016/j.jtbi.2005.10.016. PMID   16364368.
  39. ↑ Sheth R, Marcon L, Bastida MF, Junco M, Quintana L, Dahn R, Kmita M, Sharpe J, Ros MA (2012). "Hox genes regulate digit patterning by controlling the wavelength of a Turing-type mechanism". Science. 338 (6113): 1476–1480. Bibcode:2012Sci...338.1476S. doi:10.1126/science.1226804. PMC   4486416 . PMID   23239739.
  40. ↑ Zhu, J; Mackem, S (15 September 2017). "John Saunders' ZPA, Sonic hedgehog and digit identity - How does it really all work?". Developmental Biology. 429 (2): 391–400. doi:10.1016/j.ydbio.2017.02.001. PMC   5540801 . PMID   28161524.
  41. ↑ Leal F, Cohn MJ (January 2018). "Developmental, genetic, and genomic insights into the evolutionary loss of limbs in snakes". Genesis. 56 (1): e23077. doi:10.1002/dvg.23077. PMID   29095557. S2CID   4510082.
  42. ↑ Chiang C, Litingtung Y, Harris M, Simandl B, Li Y, Beachy P, Fallon J (2001). "Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function". Dev Biol. 236 (2): 421–35. doi: 10.1006/dbio.2001.0346 . PMID   11476582.
  43. ↑ Riddle RD, Ensini M, Nelson C, Tsuchida T, Jessell TM, Tabin C (1995). "'Induction of the LIM homeobox gene Lmx1b by WNT7a establishes dorsoventral pattern in the vertebrate limb". Cell. 83 (2): 631–40. doi: 10.1016/0092-8674(95)90103-5 . PMID   7585966. S2CID   16272219.
  44. ↑ Johnson RL, Tabin CJ (September 19, 1997). "Molecular Models for Vertebrate Limb Development". Cell. 90 (6): 979–990. doi: 10.1016/S0092-8674(00)80364-5 . PMID   9323126.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.