A role for FGF-8 in the initiation and maintenance of vertebrate limb bud outgrowth

Mahmood, Radma; Bresnick, Janine; Hornbruch, Amata; Mahony, Catherine; Morton, Nicola; Colquhoun, Kate; Martin, Paul; Lumsden, Andrew; Dickson, Clive; Mason, Ivor

doi:10.1016/s0960-9822(95)00157-6

Cited by 278 publications

(172 citation statements)

References 53 publications

(85 reference statements)

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“…It can recover the AER activity in embryonic limbs deprived of this structure (Mahmood et al, 1995). Although the characteristic AER has practically degenerated at the beginning of interdigital regression, we hypothesized that the observed digit growth could be due to persistent FGF-8 activity.…”

Section: Gene Expression During Interdigital Cell Deathmentioning

confidence: 93%

“…Both fgf-4 and fgf-8 are expressed in the AER, and their corresponding proteins promote cell proliferation in the underlying mesenchyme of the progress zone (Crossley and Martin, 1995;Mahmood et al, 1995), leading to limb growth in the distoproximal axis. We show that fgf-8 expression became restricted to the tip of digits at the onset of interdigital apoptosis.…”

Section: Molecular Control Of Digit Growth and Interdigital Cell Deathmentioning

confidence: 99%

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Differential tissue growth and patterns of cell death in mouse limb autopod morphogenesis

Salas‐Vidal

Valencia

Covarrubias

2001

Developmental Dynamics

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Programmed cell death (PCD) is considered one of the most important cellular processes in the morphogenesis of organs and tissues during animal development. Although the embryonic limb has been established as a classic model for the study of PCD, detailed studies on this process' contribution to morphogenesis are still lacking. In the present work, using modern computer-aided techniques, we estimated the contribution of PCD to mouse limb morphogenesis. For the detection of apoptotic cell death, we stained whole embryonic limbs with acridine orange or, in some instances, used the TUNEL technique, and visualized the tissues by confocal laser scanning microscopy. We found that cell death patterns are dynamic during limb development, and occur in gradients oriented with the main limb axes, anteroposterior, dorsoventral and distoproximal. Interdigital apoptosis in the autopod was initially detected at the most distal region, and then more proximally as development proceeded. Interestingly, we found that digit separation is more pronounced on the dorsal side, contrary to what is expected from the apoptotic cell distribution, which shows more abundant cell death in the ventral region. Using 2-D and 3-D models, we found that most digit individualization occurs rather by digit growth than by interdigital cell death. Therefore, digits do not mainly individualize by degeneration of preformed interdigital tissue, but probably by a dynamic balance between proliferation and cell death, reducing interdigital growth, which results in protrusion of digits. We determined the expression pattern of fgf-8 during the period of digit individualization, as the product of this gene could participate in defining the limb growth pattern. Initially, fgf-8 expression was coincident with the apical ectodermal ridge, but when cell death was first detected in the interdigits, fgf-8 expression became restricted to the tip of the growing digits. Therefore, FGF-8 could be one of the factors responsible for differential digit-interdigit growth, and might also act as a survival factor on interdigital tissue. We also found that the expression patterns of rar-␤, bmp-2, bmp-4, bmp-7, msx-1, and msx-2 genes, proposed to be involved in the activation of interdigital cell death, did not overlap with, or were not highly expressed in the major zones of cell death in the developing limb.

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Section: Gene Expression During Interdigital Cell Deathmentioning

confidence: 93%

Section: Molecular Control Of Digit Growth and Interdigital Cell Deathmentioning

confidence: 99%

Differential tissue growth and patterns of cell death in mouse limb autopod morphogenesis

Salas‐Vidal

Valencia

Covarrubias

2001

Developmental Dynamics

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“…Of these, Fgf8 is always expressed by AER cells, from their initial specification as AER precursors until the final regression of the AER (Crossley et al, 1996). For this reason, Fgf8 is considered the best marker of the AER (Crossley and Martin, 1995;Mahmood et al, 1995). In contrast, the expression of Fgf4, 9, and 17 is restricted to the central-posterior portion of the AER and only during the intermediate stages of AER development (Martin, 1998).…”

Section: Introductionmentioning

confidence: 99%

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

Developmental Dynamics

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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.

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“…Both fgf-4 and fgf-8 are expressed in the apical ectodermal ridge (AER) of the limb buds ( Fig. 5C and D), a region controlling proximodistal outgrowth of the buds (Niswander et al, 1993;Vogel and Tickle, 1993;Mahmood et al, 1995). FGF-10 has been shown to initiate outgrowth of the limb buds (Ohuchi et al, 1997;Sekine et al, 1999), but at these stages it is expressed in a proliferating region of the limb bud known as the progress zone (Fig.…”

Section: Trunkmentioning

confidence: 99%

Survey of fibroblast growth factor expression during chick organogenesis

et al. 2002

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Members of the extensive fibroblast growth factor (FGF) family play many key roles during embryonic development. In later development, during the course of organogenesis, these factors have been shown to direct distinct cellular pathways within the context of a particular organ system. To gain more insight into the processes that these factors may be controlling, we conducted a survey of the expression of known FGF family members in chick embryos at stages 18 -25. We show the expression patterns of

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A role for FGF-8 in the initiation and maintenance of vertebrate limb bud outgrowth

Cited by 278 publications

References 53 publications

Differential tissue growth and patterns of cell death in mouse limb autopod morphogenesis

Differential tissue growth and patterns of cell death in mouse limb autopod morphogenesis

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

Survey of fibroblast growth factor expression during chick organogenesis

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