Limb development

Limb development

The tetrapod limb develops from a specific area of the body axis called the limb field. The position of the limb field is associated with and presumably specified by the spatial pattern of Hox gene expression along the body axis. Retinoic acid also seems to plays a role in limb bud formation since pharmacological block of retinoic acid abrogates limb formation. [cite journal | author = Stratford T, Horton C, Maden M. | title = Retinoic acid is required for the initiation of outgrowth in the chick limb bud.| journal = Curr Biol | volume = 6 | issue = 9 | pages = 1124-33 | year = 1996 | pmid = 8805369 ]

Limb formation results from series of epithelial-mesenchymal inductions between the limb bud mesenchymal cells and the overlying ectodermal cells. Cells from the lateral plate mesoderm and the myotome migrate to the limb field and proliferate to create 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 a fibroblastic growth factor, presumably, FGF7 and FGF10 to induce the overlying ectoderm to form an important organizing structure called the apical ectodermal ridge (AER). [cite journal | author = Yonei-Tamura S, Endo T, Yajima H, Ohuchi H, Ide H, Tamura K. | title = FGF7 and FGF10 directly induce the apical ectodermal ridge in chick embryos. | journal = Dev Biol. | volume = 211 | issue = 1 | pages = 133-43 | year = 1999 | pmid = 10373311 ] . The AER reciprocatively secretes FGF8 and FGF4 which maintains the FGF10 signal and induces proliferation in the mesoderm.Fact|date=August 2008 The position of FGF10 expression is regulated by 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 T-box containing transcription factors: Tbx5 and Tbx4, respectively. [cite journal | author = Ohuchi H, Takeuchi J, Yoshioka H, Ishimaru Y, Ogura K, Takahashi N, Ogura T, Noji S. | title = Correlation of wing-leg identity in ectopic FGF-induced chimeric limbs with the differential expression of chick Tbx5 and Tbx4. | journal = Development. | volume = 125 | issue = 1 | pages = 51-60 | year = 1998 | pmid = 9389663 ] [cite journal | author = Rodriguez-Esteban C, Tsukui T, Yonei S, Magallon J, Tamura K, Izpisua Belmonte JC. | title = The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity.| journal = Nature. | volume = 398 | issue = 6730 | pages = 814-8 | year = 1999 | pmid = 10235264 ]

Programmed cell death removes the spaces between the digits and joints. BMP signaling induces cell death and Noggin blocks cell death in the digits.Fact|date=August 2008

Precartilage condensations

The limb's skeletal elements are prefigured by tight aggregates of mesenchymal cells called "precartilage condensations". Mesenchymal condensation is mediated by extracellular matrix and cell adhesion molecules. [cite journal | author = Hall BK, Miyake T | title = All for one and one for all: condensations and the initiation of skeletal development. | journal = BioEssays | volume = 22 | issue = 2 | pages = 138-47 | year = 2000 | pmid = 10655033 ] Cartilage differentiates from the condensations, giving rise to the skeletal primordia. In most tetrapod limb skeletons (though not in some amphibians), the cartilage skeleton is replaced by bone later in development.

Periodicities of the limb pattern

The limb is organized into three regions: stylopod, zeugopod, and autopod (in order from proximal to distal). Within the distal two of these regions the skeleton contains a number of periodic and quasi-periodic pattern motifs. The zeugopod consists of two parallel elements along the anteroposterior (AP) 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 (PD) 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.cite journal | author = Newman SA, Bhat R | title = Activator-inhibitor dynamics of vertebrate limb pattern formation. | journal = Birth Defects Res C Embryo Today | volume = 81 | issue = 4 | pages = 305-19 | year = 2007 | pmid = 18228262 ]

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

Axial patterning and related issues

Many investigations into the development of the limb skeletal pattern have been influenced by the "positional information" paradigm developed by Lewis Wolpert in 1971. [cite journal | author = Wolpert L | title = Positional information and pattern formation. | journal = Curr Top Dev Biol. | volume = 6 | issue = 6 | pages = 183-224 | year = 1971 | pmid = 4950136 ] In tune with this paradigm, efforts have been made to identify diffusive signaling molecules known as morphogens which traverse orthogonal axes of developing limbs and impart specific identities to cells based on their concentrations. It must be noted, however, that limb mesenchymal cells, when dissociated and grown in culture or reintroduced within limbs can recapitulate essential aspects of pattern formation, morphogenesis and differentiation. [cite journal | author = Ros MA, Lyons GE, Mackem S, Fallon JF. | title = Recombinant limbs as a model to study homeobox gene regulation during limb development. | journal = Dev Biol. | volume = 166 | issue = 1 | pages = 59-72 | year = 2007 | pmid = 7958460 ] Thus, the axes-specifying morphogens may be also be looked upon as stabilizers and fine-tuners of a ubiquitous morphodynamic cartilage-skeleton forming program.

Proximal/distal patterning

Hox genes contribute to the specification of the stylopod, zeugopod and autopod. Mutations in Hox genes lead to proximal/distal losses or abnormalities [cite journal | author = Wellik D, Capecchi M | title = Hox10 and Hox11 genes are required to globally pattern the mammalian skeleton. | journal = Science | volume = 301 | issue = 5631 | pages = 363–7 | year = 2003 | pmid = 12869760 | doi = 10.1126/science.1085672] . Two competing models have been advanced for explaining the patterning of these regions.

Progress Zone model

The AER creates a zone of cell proliferation and lays down the limb from proximal to distal. The time cells leave the AER determines their positional value. Proximal structures are formed earlier than distal structures.

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

"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 a new bud tip on top of an old bud tip results in a deletion and duplication 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 200μm zone adjacent to the AER when removed--cell death removes some patterning. FGF beads are able to rescue limb development by preventing cell death.

"Experimental evidence:"
* Labeled cells in different position of an early limb bud were restricted to single segments of the limb. [cite journal | author = Dudley A, Ros M, Tabin C | title = A re-examination of proximodistal patterning during vertebrate limb development. | journal = Nature | volume = 418 | issue = 6897 | pages = 539–44 | year = 2002 | pmid = 12152081 | doi = 10.1038/nature00945]
* Limbs lacking expression of required FGF4 & FGF8 showed all structures of the limb and not just the proximal parts [cite journal | author = Sun X, Mariani F, Martin G | title = Functions of FGF signalling from the apical ectodermal ridge in limb development. | journal = Nature | volume = 418 | issue = 6897 | pages = 501–8 | year = 2002 | pmid = 12152071 | doi = 10.1038/nature00902] .

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. [cite journal | author = Tabin C, Wolpert L | title = Rethinking the proximodistal axis of the vertebrate limb in the molecular era. | journal = Genes Dev. | volume = 21 | issue = 12 | pages = 1433-42 | year = 2007 | pmid = 17575045]

Anterior/posterior patterning

The Zone of Polarizing Activity (ZPA) in the limb bud has pattern-organizing activity by action of a morphogen gradient of Sonic hedgehog (Shh). Shh is both sufficient and necessary to create the ZPA and specify the anterior/posterior 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 though 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 anterior/posterior axis. Loss of the Gli3 repressor leads to the formation of generic (unpatterned) digits in extra quantities [cite journal | author = Chiang C, Litingtung Y, Harris M, Simandl B, Li Y, Beachy P, Fallon J | title = Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function. | journal = Dev Biol | volume = 236 | issue = 2 | pages = 421–35 | year = 2001 | pmid = 11476582 | doi = 10.1006/dbio.2001.0346] .

Dorsal/ventral patterning

Dorsal/Ventral Patterning arises from Wnt7a signals in the overlying ectoderm not the mesoderm. Wnt7a is both necessary and sufficient to dorsalize the limb. Wnt7a also influences the anterior/posterior axis 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.

Wnt-7a also causes Lmx-1, a Lim Hox gene (and thus a transcription factor), to be expressed. Lmx-1 is involved in dorsalisation of the limb, which was shown by knocking out the Lmx-1 gene in mice [cite journal | author = Riddle RD, Ensini M, Nelson C, Tsuchida T, Jessell TM, Tabin C| title = 'Induction of the LIM homeobox gene Lmx1 by WNT7a establishes dorsoventral pattern in the vertebrate limb | journal = Cell | volume = 17;83(4) | issue = 2 | pages = 631-40 | year = 1995 | pmid = 7585966] . The mice lacking the Lmx-1 produced ventral skin on both sides of their paws. There are other factors thought to control the DV patterning; Engrailed-1 is involved in the formation of the ventral side of the limbs [] .


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