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. 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. 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. 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. 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. Because these signaling systems reciprocally sustain each other’s activity, limb development is essentially autonomous after these signaling regions have been established. Limb bud Limb formation begins in the morphogenetic limb field.

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Related concepts (4)
French flag model
The French flag model is a conceptual definition of a morphogen, described by Lewis Wolpert in the 1960s. A morphogen is defined as a signaling molecule that acts directly on cells (not through serial induction) to produce specific cellular responses dependent on morphogen concentration. During early development, morphogen gradients generate different cell types in distinct spatial order. French flag patterning is often found in combination with others: vertebrate limb development is one of the many phenotypes exhibiting French flag patterning overlapped with a complementary pattern (in this case Turing pattern).
Limb bud
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. The limb bud consists of undifferentiated mesoderm cells that are sheathed in ectoderm.
Sonic hedgehog protein
Sonic hedgehog protein (SHH) is encoded for by the SHH gene. The protein is named after the character Sonic the Hedgehog. This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organogenesis and the organization of the central nervous system, limbs, digits and many other parts of the body. Sonic hedgehog is a morphogen that patterns the developing embryo using a concentration gradient characterized by the French flag model.
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