Fgf8 signalling from the AER is essential for normal limb development

@article{Lewandoski2000Fgf8SF,
  title={Fgf8 signalling from the AER is essential for normal limb development},
  author={Mark Lewandoski and Xin Sun and Gail Roberta Martin},
  journal={Nature Genetics},
  year={2000},
  volume={26},
  pages={460-463}
}
Vertebrate limb development depends on signals from the apical ectodermal ridge (AER), which rims the distal tip of the limb bud. Removal of the AER in chick results in limbs lacking distal skeletal elements. Fibroblast growth factor (FGF) proteins can substitute for the AER (refs 4–7), suggesting that FGF signalling mediates AER activity. Of the four mouse Fgf genes (Fgf4 , Fgf8, Fgf9, Fgf17) known to display AER-specific expression domains within the limb bud (AER-Fgfs), only Fgf8 is… 
Genetic evidence that FGFs have an instructive role in limb proximal–distal patterning
TLDR
Analysis of the compound mutant limb buds revealed that, in addition to sustaining cell survival, AER-FGFs regulate P–D-patterning gene expression during early limb bud development, providing genetic evidence that A ER-F GFs function to specify a distal domain and challenging the long-standing hypothesis that AER -FGF signalling is permissive rather than instructive for limb patterning.
FGF signaling regulates mesenchymal differentiation and skeletal patterning along the limb bud proximodistal axis
TLDR
It is concluded that chondrogenic primordia formation, marked by initial Sox9 expression in limb mesenchyme, is an essential component of the PD patterning process and that a key role for AER-FGF signaling is to facilitate SOX9 function and to ensure progressive establishment of chondroblast growth factors along the PD axis.
Functions of FGF signalling from the apical ectodermal ridge in limb development
TLDR
It is shown that FGF4 and FGF8 regulate cell number in the nascent limb bud and are required for survival of cells located far from the AER, and these functions are essential to ensure that sufficient progenitor cells are available to form the normal complement of skeletal elements, and perhaps other limb tissues.
Increasing Fgf4 expression in the mouse limb bud causes polysyndactyly and rescues the skeletal defects that result from loss of Fgf8 function
TLDR
It is demonstrated that FGF4 can functionally replace FGF8 in limb skeletal development, and the increase in FGF signaling that occurs when the Fgf4 gain-of-function allele is activated in a wild-type limb bud causes formation of a supernumerary posterior digit, as well as cutaneous syndactyly between all the digits.
Fibroblast Growth Factor 10 and Vertebrate Limb Development
TLDR
The observed limb phenotype is similar to the severe proximal truncations observed in human babies exposed to thalidomide, which has been proposed to block the Fgf10-AER-Fgf8 feedback loop.
Fgf-signaling is compartmentalized within the mesenchyme and controls proliferation during salamander limb development
TLDR
Investigation of how Sonic hedgehog and Fibroblast growth factor signaling regulate limb development in the axolotl found that Shh-expressing cells contributed to the most posterior digit, and that inhibiting ShH-signaling inhibited Fgf8 expression, anteroposterior patterning, and distal cell proliferation.
Canonical Wnt Signaling and the Regulation of Divergent Mesenchymal Fgf8 expression in Axolotl Limb Development and Regeneration
TLDR
The hypothesis that alterations to one or more of these components during evolution has resulted in mesenchymal Amex.Fgf8 in axolotl has been addressed, which implicate a shift in tissue responsiveness to canonical Wnt signaling from epidermis to mesenchyme as one step contributing to the unique mesenchcyal AmEx.
Growth arrest specific gene 1 acts as a region-specific mediator of the Fgf10/Fgf8 regulatory loop in the limb.
TLDR
It is shown that the growth arrest specific gene 1 (Gas1) is required in the mesenchyme for the normal regulation of Fgf10/Fgf8, and evidence is provided that Gas1 acts to maintain high levels of FGF10 at the tip mesenchYme and support the proposal that FgF10 expression in this region is crucial for maintaining Fg f8 expression in the AER.
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References

SHOWING 1-10 OF 30 REFERENCES
Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development
TLDR
A model in which no individual Fgf expressed in the AER (AER–Fgf) is solely necessary to maintain Shh expression, but, instead, the combined activities of two or more AER–fgfs function in a positive feedback loop with Shh to control limb development is discussed.
Normal limb development in conditional mutants of Fgf4.
TLDR
Findings indicate that the previously proposed FGF4-SHH feedback loop is not essential for coordination of murine limb outgrowth and patterning and suggest that some of the roles currently attributed to F GF4 during early vertebrate limb development may be performed by other AER factors in vivo.
BMPs negatively regulate structure and function of the limb apical ectodermal ridge.
TLDR
It is found that BMPs limit limb outgrowth by promoting AER regression, as BMP inhibition results in persistence of the AER, prolonged Fgf expression and excess soft-tissue growth.
Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds
TLDR
This study uncovers the cascade by which the SHH signal is relayed from the posterior mesenchyme to the AER and establishes that Formin-dependent activation of the BMP antagonist Gremlin is sufficient to induce Fgf4 and establish theSHH/FGF4 feedback loop.
Fgf8 is required for outgrowth and patterning of the limbs
TLDR
It is reported that conditional disruption of Fgf8 in the forelimb of developing mice bypasses embryonic lethality and reveals a requirement for FgF8 inThe formation of the stylopod, anterior zeugopod and autopod.
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