Vertebrate Embryo: Limb Development

AbstractVertebrate limbs develop from small buds of mesenchyme cells encased in ectoderm. Limb development is an excellent model system for studying embryonic growth and pattern formation. Both processes are governed by cell–cell interactions involving signalling centres that operate along each of the three limb axes, but are functionally interconnected. The main proliferative and positional signals are WNTs, FGFs, SHH and BMPs. Considerable progress has been made in identifying molecules that initiate bud formation including the TBX4/5 transcription factors and unravelling the regulatory pathways that establish the signalling centres.Hoxgenes are involved in multiple steps in establishing the anteroposterior signalling centre in the forelimb. They are also expressed in response to positional signals in the limb buds with a late‐phase controlling digit development. The transcription factor, LMX1B, specifies dorsal development. The transcription factor PITX1 is a major hindlimb determinant but how positional information is interpreted is largely unknown.Key ConceptsThe limb develops from a bud of mesoderm cells encased in ectoderm which grows out from the body wall.The limb bud mesoderm is made up of cells with two different origins; cells of the lateral plate mesoderm which give rise to the connective tissues and cells that have migrated from the somites which give rise to the myogenic cells of the limb muscles.Three sets of cell–cell interactions specify positional information; one set of interactions operating along each of the three axes of the limb.The apical ectodermal ridge at the tip of the limb bud produces FGFs which are required for bud outgrowth and laying down the proximodistal limb pattern.The dorsal and ventral ectoderm of the limb bud produce WNT7a and BMPs, respectively, which are involved in specifying dorsoventral positional information.The polarising region, a mesodermal signalling region at the posterior margin of the limb bud, produces Sonic Hedgehog (SHH) which specifies anteroposterior positional information and controls growth across this axis.Hox5andHox9paralogous genes of theHoxclusters are involved in establishing the initial anteroposterior polarity of the buds that will develop into forelimbs.Interactions between the signalling regions ensure that pattern formation is integrated along all three axes of the developing limb.5′ genes in theHoxAandHoxDclusters are expressed in early and late limb buds under the control of long‐range enhancers located, respectively, 3′ and 5′ of the cluster, with the early phase of activity being involved in establishingShhexpression in the polarising region and the later phase development of the digits.The differences between forelimbs and hindlimbs depend on the interpretation of positional information, with the transcription factor PITX1 being a major hindlimb determinant.