Functions of FGF signalling from the apical ectodermal ridge in limb development

Identifying the genetic basis of human limb malformation disorders has been instrumental in improving our understanding of limb development. Abnormalities of the hands and/or feet include defects affecting patterning, establishment, elongation, and segmentation of cartilaginous condensations, as well as growth of the individual skeletal elements. While the phenotype of such malformations is highly diverse, the mutations identified to date cluster in genes implicated in a limited number of molecular pathways, namely hedgehog, Wnt, and bone morphogenetic protein. The latter pathway appears to function as a key molecular network regulating different phases of digit and joint development. Studies in animal models not only extended our insight into the pathogenesis of these conditions, but have also contributed to our understanding of the in vivo functions and interactions of these key players. This review is aimed at integrating the current understanding of human digit malformations into the increasing knowledge of the molecular mechanisms of digit development. Developmental Dynamics 240:990-1004,

Section: Overviewmentioning

confidence: 99%

Mechanisms of digit formation: Human malformation syndromes tell the story

Stricker

Mundlos

2011

“…The AER exerts its action through the expression of several members of the Fibroblast growth factor (FGF) family (Martin, 1998;Moon and Capecchi, 2000;Sun et al, 2002;Boulet et al, 2004). Fgf4, 8, 9, and 17 are expressed in AER cells, in a similar pattern in mouse and in chick.…”

Section: Introductionmentioning

confidence: 99%

“…Reciprocally, the drastic reduction in FGF signaling from the AER produced by the simultaneous removal of Fgf8 and Fgf4, the two FGFs with the strongest expression in the AER, results in the failure to form a limb (Sun et al, 2002;Boulet et al, 2004). FGFs can even trigger the whole cascade of events that leads to the development of a supernumerary limb when applied to a responding tissue such as the flank (Cohn et al, 1995;Isaac et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…The single targeted deletion of Fgf4, Fgf9, or Fgf17 had no consequences for limb development indicating that other Fgf family members, particularly Fgf8, provide sufficient FGF signaling for normal limb development (Moon and Capecchi, 2000;Xu et al, 2000;Colvin et al, 2001;Sun et al, 2002). In contrast, the conditional elimination of Fgf8 from the limb ectoderm, which has been performed with three different Cre lines, resulted in hypoplastic limbs whose phenotype depended on the specific Cre line used (Lewandoski et al, 2000;Moon and Capecchi, 2000;Boulet et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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The incomplete inactivation of Fgf8 in the limb ectoderm affects the morphogenesis of the anterior autopod through BMP‐mediated cell death

Delgado

Domínguez-Frutos

Schimmang

et al. 2008

Here we analyze limb development after the conditional inactivation of Fgf8 from the epiblast, using the previously described MORE (Mox2Cre) line. This line drives variable mosaic recombination of a floxed Fgf8 allele, resulting in a small proportion of AER cells that maintain Fgf8 expression. The phenotype of Mox2Cre;Fgf8 limbs is most similar to that of Msx2Cre;Fgf8 forelimbs, indicating that a small but durable expression of FGF8 is equivalent to an early normal, but transitory, expression. This functional equivalence likely relies on the subsequent Fgf4 upregulation that buffers the differences in the pattern of Fgf8 expression between the two conditional mutants. The molecular analysis of Mox2Cre;Fgf8 limbs shows that, despite Fgf4 upregulation, they develop under reduced FGF signaling. These limbs also exhibit an abnormal area of cell death at the anterior forelimb autopod, overlapping with an ectopic domain of Bmp7 expression, which can explain the abnormal morphogenesis of the anterior autopod. Developmental Dynamics 237: 649 -658, 2008.

“…Pr-D growth Wrist and digit elements greatly reduced (Sun et al, 2002) Upstream Known for Fgf4 (Fraidenraich et al, 1998) Grem1 Pr-D growth/AER maintenance Reduced digit number (Khokha et al, 2003) Downstream Known (Zuniga et al, 2004) Wnt7a Dorsal and posterior limb development Loss of dorsal phenotype and posterior most digits (Adamska et al, 2005) Upstream or parallel…”

Section: Fgf4/fgf8mentioning

confidence: 99%

Evolution of vertebrate appendicular structures: Insight from genetic and palaeontological data

Abbasi

2011

The new body of evidence from fossils and comparative-developmental analysis of subset of appendicular patterning genes has revealed that limb elements seen in tetrapods are assembled in fish fin over evolutionary time. However, despite of deep homology in basic structure and underlying developmental system, there remains a large morphological gap between distal elements of tetrapod limb and distal fin skeleton of tetrapodomorph fish. Understanding the genetic basis of major transformations in distal-limb morphology is the next challenge for evolutionary developmental biologists. Here by integrating data from fossils, comparative-developmental and genetic studies, models are proposed describing the evolution of cis-regulatory elements as a basis for diversification of appendicular architecture. Instead of emphasizing the subset of developmental genes, for instance Hoxd genes, the focus here is on the significance of elucidating cis-regulatory elements for multiple other key molecular players of limb/fin development and genetic/ molecular interactions among them, for a better understanding of the developmental and genetic basis of limb evolution. Developmental Dynamics 240:1005-1016,