A positive feedback loop coordinates growth and patterning in the vertebrate limb

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Point mutations in the intronic ZRS region of Lmbr1, a limb specific cis-regulatory element of Sonic hedgehog (Shh), are associated with polydactyly in humans, cats, and mice. We and others have recently mapped the dominant preaxial polydactyly (Po) locus in Silkie chickens to a single nucleotide polymorphism (SNP) in the ZRS region. Using polymorphisms in the chicken Shh sequence, we confirm that the ZRS region directly regulates Shh expression in the developing limb causing ectopic Shh expression in the anterior leg, prolonged Shh expression in the posterior limb, and allelic imbalance between wt and Slk Shh alleles in heterozygote limbs. Using Silkie legs, we have explored the consequences of increased Shh expression in the posterior leg on the patterning of the toes, and the induction of preaxial polydactyly.

“…Probes were made from the following templates: Fgf4 (Niswander et al, 1994), Fgf8 (Crossley et al, 1996), Gli1, Gli2 (Marigo et al, 1996a), Gremlin (Merino et al, 1999) …”

Section: Wholemount Rna In Situ Hybridisationmentioning

confidence: 99%

The chicken polydactyly (Po) locus causes allelic imbalance and ectopic expression of Shh during limb development

Dunn

Paton

Clelland

et al. 2011

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“…2B). Shh is necessary to maintain the AER posteriorly (Laufer et al, 1994;Niswander et al, 1994). This maintenance is mediated by the inhibition of BMP activity (Bmp2, Bmp4, Bmp7), an anti-AER factor, through the production of Gremlin Khokha et al, 2003;Michos et al, 2004).…”

Section: Downstream Shh: Life and Death In The Limb Fieldmentioning

confidence: 99%

Anteroposterior patterning in the limb and digit specification: Contribution of mouse genetics

Robert

Lallemand

2006

The limb has been a privileged object of investigation and reflection for scientists over the past two centuries and continues to provide a heuristic framework to analyze vertebrate development. Recently, accumulation of new data has significantly changed our view on the mechanisms of limb patterning, in particular along the anterior-posterior axis. These data have led us to revisit the mode of action of the zone of polarizing activity. They shed light on the molecular and cellular mechanisms of patterning linked to the Shh-Gli3 signaling pathway and give insights into the mechanism of activation of these cardinal factors, as well as the consequences of their activity. These new data are in good part the result of systematic Application of tools used in contemporary mouse molecular genetics. These have extended the power of mouse genetics by introducing mutational strategies that allow fine-tuned modulation of gene expression, interchromosomal deletions and duplication. They have even made the mouse embryo amenable to cell lineage analysis that used to be the realm of chick embryos. In this review, we focus on the data acquired over the last five years from the analysis of mouse limb development and discuss new perspectives opened by these results. Developmental Dynamics 235:2337-2352, 2006.

“…In addition FGF-4 maintains the expression of several genes in the posterior mesenchyme and can also maintain polarizing activity of the limb bud (Niswander et al, 1993(Niswander et al, , 1994Vogel and Tickle, 1993). F g f 4 and shh expression act in a loop with each able to maintain the expression of the other (Niswander et al, 1994;Laufer et al, 1994). However, the intermediate signals have not yet been identified.…”

Section: Expression Of Bmp Genes In the Talpid3 Limbmentioning

confidence: 99%

“…Fgf4 transcripts are found in the posterior part of the apical ectodermal ridge, and FGF-4 protein can maintain the expression of these genes and outgrowth of the limb bud in the absence of the apical ectodermal ridge (Niswander et al, 1993(Niswander et al, , 1994Laufer et al, 1994). Shh also appears to regulate Fgf-4 expression in the ridge, thus establishing a feedback loop that coordinates signalling between the mesenchyme and epithelium a t the posterior margin of the limb bud (Niswander et al, 1994;Laufer et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Expression of genes encoding bone morphogenetic proteins and sonic hedgehog in talpid (ta³) limb buds: Their relationships in the signalling cascade involved in limb patterning

Francis‐West

Robertson

Ede

et al. 1995

111

The chicken mutant talpid3 (tu3) has polydactylous limbs with up to 7-8 morphologically similar digits. This lack of antero-posterior polarity in digit pattern is correlated with symmetrical expression of genes of the HoxD complex. We determined the distribution of polarizing activity in limb buds of the chick mutant tu3 by assessing the ability of mesenchyme from various positions along the antero-posterior axis to induce digit duplications when grafted anteriorly into a normal limb. Cells with highest polarizing activity were found at the posterior margin of the wing as in the polarizing region of normal limb buds. However, in contrast to normal limb buds, tu3 anterior mesenchyme also had low polarizing activity. Application of retinoic acid or a polarizing region graft to the anterior of tu3 limb buds changed digit morphology but did not induce digit duplications or digits with any characteristic a-p pattern. To determine which genes are associated with polarizing activity and which are associated with patterning of the digits, we examined expression of the genes Sonic hedgehog (shh), Bmp-2, and Bmp-7, whose expression is normally confined to the posterior margin of the early wing bud and is associated with the polarizing region. In addition, we determined the distribution of Fgf-4 transcripts which in normal limb buds are restricted to the posterior part of the apical ectoderma1 ridge. In tu3 limb buds, shh expression is restricted to the posterior limb mesenchyme, which has high polarizing activity, but is not expressed in regions which have low polarizing activity. In contrast, Bmp-2 and Bmp-7 are expressed uniformly along the a-p axis. Fgf4 transcripts are present throughout the apical ectodermal ridge in tu3 limb buds. In the tu3 mutant, there is both an abnormal distribution of signalling activity and response to polarizing signals. In addition, the dissociation between the expression of shh and Bmps suggests distinct roles for the encoded molecules in signalling and response in a-p patterning of limb buds. o 1995 Wiley-Liss, Inc.