Transient downregulation of Bmp signalling induces extra limbs in vertebrates

Christen, Bea; Rodrigues, Alexandre Miguel Cavaco; Monasterio, Monserrat Barragán; Roig, Carme Fabregat; Belmonte, Juan Carlos Izpisúa

doi:10.1242/dev.078774

Cited by 13 publications

(23 citation statements)

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“…2). This phenotype has recently been described and characterized by others (Christen et al 2012). Ectopic limb formation was somewhat dependent on genetic background, occurring frequently in some tadpole cohorts but absent from others.…”

Section: Noggin Overexpression Can Results In the Formation Of Ectopicmentioning

confidence: 53%

“…The number of ectopic limbs varied from a single extra limb to three extra limbs, with no more than two limbs in total developing at one site. Ectopic limbs were only ever observed in N1 tadpoles exposed to heat-shock treatments from stage 50, spanning stage 51, slightly later than those described by Christen et al (2012). WT limbs treated in the same way never developed ectopic limbs.…”

Section: Noggin Overexpression Can Results In the Formation Of Ectopicmentioning

confidence: 68%

“…The ectopic limbs have been extensively examined for limb patterning gene expression by Christen et al (2012), who confirmed that the limb duplication arises from expansion of the dorsal domain, resulting in formation of a ventrally placed secondary limb with normal DV pattern, and in dorsalization of the original limb, with each limb maintaining its own AER expressing fgf8 (Fig. 2E,F).…”

Section: Noggin Overexpression Can Results In the Formation Of Ectopicmentioning

confidence: 87%

“…Very early limb buds appeared to be refractory to the effects of BMP attenuation, developing normally in most cases. Ectopic limbs were produced by overexpression of Noggin corresponding to a brief window of limb development at about stage 49/50, as recently described by Christen et al (2012). Attenuation of BMP signaling in stage 51 or 52 tadpoles lead to a reduction in the number of digits formed, resulting in hypodactyly or ectrodactyly, as well as occasional defects in the more proximal tibiafibula.…”

Section: Introductionmentioning

confidence: 99%

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Attenuation of bone morphogenetic protein signaling during amphibian limb development results in the generation of stage‐specific defects

2013

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The vertebrate limb is one of the most intensively studied organs in the field of developmental biology. Limb development in tetrapod vertebrates is highly conserved and dependent on the interaction of several important molecular pathways. The bone morphogenetic protein (BMP) signaling cascade is one of these pathways and has been shown to be crucial for several aspects of limb development. Here, we have used a Xenopus laevis transgenic line, in which expression of the inhibitor Noggin is under the control of the heatshock promoter hsp70 to examine the effects of attenuation of BMP signaling at different stages of limb development. Remarkably different phenotypes were produced at different stages, illustrating the varied roles of BMP in development of the limb. Very early limb buds appeared to be refractory to the effects of BMP attenuation, developing normally in most cases. Ectopic limbs were produced by overexpression of Noggin corresponding to a brief window of limb development at about stage 49/50, as recently described by Christen et al. (2012). Attenuation of BMP signaling in stage 51 or 52 tadpoles lead to a reduction in the number of digits formed, resulting in hypodactyly or ectrodactyly, as well as occasional defects in the more proximal tibiafibula. Finally, inhibition at stage 54 (paddle stage) led to the formation of dramatically shortened digits resulting from loss of distal phalanges. Transcriptome analysis has revealed the possibility that more Nogginsensitive members of the BMP family could be involved in limb development than previously suspected. Our analysis demonstrates the usefulness of heat-shock-driven gene expression as an effective method for inhibiting a developmental pathway at different times during limb development.

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Section: Noggin Overexpression Can Results In the Formation Of Ectopicmentioning

confidence: 53%

Section: Noggin Overexpression Can Results In the Formation Of Ectopicmentioning

confidence: 68%

Section: Noggin Overexpression Can Results In the Formation Of Ectopicmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Attenuation of bone morphogenetic protein signaling during amphibian limb development results in the generation of stage‐specific defects

2013

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“…5). Recent studies showed that either activation of Wnt signaling or transient inactivation of Bmp signaling can lead to ectopic digit/fin formation in other vertebrates and increased sp8 expression was evident in both situations (18,37). Although ecl mutants did not survive until metamorphosis, we found that embryos injected unilaterally with sp8 TALEN showed limb outgrowth defects (Fig.…”

Section: Discussionmentioning

confidence: 56%

Sp8 regulates inner ear development

Chung

Medina-Ruiz

Harland

2014

Proc. Natl. Acad. Sci. U.S.A.

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A forward genetic screen of N-ethyl-N-nitrosourea mutagenized Xenopus tropicalis has identified an inner ear mutant named eclipse (ecl). Mutants developed enlarged otic vesicles and various defects of otoconia development; they also showed abnormal circular and inverted swimming patterns. Positional cloning identified specificity protein 8 (sp8), which was previously found to regulate limb and brain development. Two different loss-of-function approaches using transcription activator-like effector nucleases and morpholino oligonucleotides confirmed that the ecl mutant phenotype is caused by down-regulation of sp8. Depletion of sp8 resulted in otic dysmorphogenesis, such as uncompartmentalized and enlarged otic vesicles, epithelial dilation with abnormal sensory end organs. When overexpressed, sp8 was sufficient to induce ectopic otic vesicles possessing sensory hair cells, neurofilament innervation in a thickened sensory epithelium, and otoconia, all of which are found in the endogenous otic vesicle. We propose that sp8 is an important factor for initiation and elaboration of inner ear development.T he vertebrate inner ear is a sensory organ responsible for balance and sound detection. Dysfunction of the inner ear is among the most common congenital disorders, affecting at least 1 in 500 births (1) and ∼40% of sensorineural deafness is associated with inner ear malformations (2). However, the study of hearing and balance impairment in humans is limited by the inability to follow inner ear development. Vertebrates share similarities in the sequence of developmental events that form the inner ear: the formation of an otic placode from an ectodermal thickening, morphogenesis to form the otocyst, and regional patterning of the otic vesicle (OV), resulting in the 3D membranous labyrinth (3, 4). Multipotent sensory progenitor cells are induced in the ectoderm surrounding the anterior neural plate, a domain termed the preplacodal region (PPR), and six1 has been characterized as marking this panplacodal domain. Signals from hindbrain and the regional expression of different transcription factors differentiate the PPR into the otic placode. The OV is partitioned by asymmetrical expression of various developmental regulators to pattern subdomains of the developing inner ear.The abilities of Xenopus to elucidate the cellular and molecular aspects of developmental processes position it as a valuable model organism (5-7). Earlier studies of lineage analysis and spatiotemporal expression of transcription factors during inner ear development led to construction of an inner ear fate map in Xenopus and this fate map allows us to interpret gene expression patterns within the context of the anatomy (8, 9). In recent years, genetic and genomic approaches have been developed in Xenopus tropicalis (10-13). To advance our understanding of inner ear development, we have screened N-ethyl-N-nitrosourea (ENU) mutagenized X. tropicalis colonies and recovered an inner ear mutant named eclipse (ecl). The ecl mutant perturbs specificity protei...

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Xenopus Limb bud morphogenesis

Keenan

Beck

2015

Developmental Dynamics

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Xenopus laevis, the South African clawed frog, is a well-established model organism for the study of developmental biology and regeneration due to its many advantages for both classical and molecular studies of patterning and morphogenesis. While contemporary studies of limb development tend to focus on models developed from the study of chicken and mouse embryos, there are also many classical studies of limb development in frogs. These include both fate and specification maps, that, due to their age, are perhaps not as widely known or cited as they should be. This has led to some inevitable misinterpretations-for example, it is often said that Xenopus limb buds have no apical ectodermal ridge, a morphological signalling centre located at the distal dorsal/ventral epithelial boundary and known to regulate limb bud outgrowth. These studies are valuable both from an evolutionary perspective, because amphibians diverged early from the amniote lineage, and from a developmental perspective, as amphibian limbs are capable of regeneration. Here, we describe Xenopus limb morphogenesis with reference to both classical and molecular studies, to create a clearer picture of what we know, and what is still mysterious, about this process. Developmental Dynamics 245:233-243, 2016. V C 2015 Wiley Periodicals, Inc.

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Transient downregulation of Bmp signalling induces extra limbs in vertebrates

Cited by 13 publications

References 58 publications

Attenuation of bone morphogenetic protein signaling during amphibian limb development results in the generation of stage‐specific defects

Attenuation of bone morphogenetic protein signaling during amphibian limb development results in the generation of stage‐specific defects

Sp8 regulates inner ear development

Xenopus Limb bud morphogenesis

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