Divergent transcriptional activities determine limb identity

Ouimette, Jean-François; Jolin, Marisol Lavertu; L’honoré, Aurore; Gifuni, Anthony J.; Drouin, Jacques

doi:10.1038/ncomms1036

Cited by 54 publications

(51 citation statements)

References 42 publications

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“…Together, these data demonstrate that Pitx1 determines hindlimb morphology independently of Tbx4. Our results differ from those recently published by Ouimette and colleagues (Ouimette et al, 2010) who have proposed that a unique Tbx4 repressor activity is the primary effector of hindlimb identity. This study used a similar transgene gene replacement strategy in the background of a Pitx1 mutant.…”

Section: Pitx1 Shapes Hindlimb Morphologies Independently Of Tbx4 Actcontrasting

confidence: 99%

Pitx1 is necessary for normal initiation of hindlimb outgrowth through regulation of Tbx4 expression and shapes hindlimb morphologies via targeted growth control

Duboc¹,

Logan²

2011

Development

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SUMMARYThe forelimbs and hindlimbs of vertebrates are morphologically distinct. Pitx1, expressed in the hindlimb bud mesenchyme, is required for the formation of hindlimb characteristics and produces hindlimb-like morphologies when misexpressed in forelimbs. Pitx1 is also necessary for normal expression of Tbx4, a transcription factor required for normal hindlimb development. Despite the importance of this protein in these processes, little is known about its mechanism of action. Using a transgenic gene replacement strategy in a Pitx1 mutant mouse, we have uncoupled two discrete functions of Pitx1. We show that, firstly, this protein influences hindlimb outgrowth by regulating Tbx4 expression levels and that, subsequently, it shapes hindlimb bone and soft tissue morphology independently of Tbx4. We provide the first description of how Pitx1 sculpts the forming hindlimb skeleton by localised modulation of the growth rate of discrete elements.

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Section: Pitx1 Shapes Hindlimb Morphologies Independently Of Tbx4 Actcontrasting

confidence: 99%

Pitx1 is necessary for normal initiation of hindlimb outgrowth through regulation of Tbx4 expression and shapes hindlimb morphologies via targeted growth control

Duboc¹,

Logan²

2011

Development

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“…Therefore, we examined the expression of the hindlimb fieldspecific genes Pitx1 and Tbx4 in order to assess a possible role of Islet1 in the specification of limb identity. Genetic analysis has suggested that Tbx4 expression is driven by the hindlimb-specific program, although its role in hindlimb specificity remains controversial (Minguillon et al, 2005;Naiche and Papaioannou, 2007;Ouimette et al, 2010). We observed a slightly weaker signal for Pitx1 expression and significant downregulation of Tbx4 in the LPM (Fig.…”

Section: Islet1 Regulates Expression Of Tbx4 But Not Pitx1 In the Lpmmentioning

confidence: 71%

Islet1-mediated activation of the β-catenin pathway is necessary for hindlimb initiation in mice

et al. 2011

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SUMMARYThe transcriptional basis of vertebrate limb initiation, which is a well-studied system for the initiation of organogenesis, remains elusive. Specifically, involvement of the -catenin pathway in limb initiation, as well as its role in hindlimb-specific transcriptional regulation, are under debate. Here, we show that the -catenin pathway is active in the limb-forming area in mouse embryos. Furthermore, conditional inactivation of -catenin as well as Islet1, a hindlimb-specific factor, in the lateral plate mesoderm results in a failure to induce hindlimb outgrowth. We further show that Islet1 is required for the nuclear accumulation of -catenin and hence for activation of the -catenin pathway, and that the -catenin pathway maintains Islet1 expression. These two factors influence each other and function upstream of active proliferation of hindlimb progenitors in the lateral plate mesoderm and the expression of a common factor, Fgf10. Our data demonstrate that Islet1 and -catenin regulate outgrowth and Fgf10-Fgf8 feedback loop formation during vertebrate hindlimb initiation. Our study identifies Islet1 as a hindlimb-specific transcriptional regulator of initiation, and clarifies the controversy regarding the requirement of -catenin for limb initiation.

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“…Islet1 appears to not be required for establishing hindlimb bud-specific characters Pitx1, a homeodomain protein, is required and sufficient for determining hindlimb-specific characters (DeLaurier et al, 2006;Lanctot et al, 1999;Logan and Tabin, 1999;Szeto et al, 1999), whereas the role of Tbx4, a T-box transcription factor, in hindlimb specification remains controversial (Minguillon et al, 2005;Naiche and Papaioannou, 2007;Ouimette et al, 2010). Localized expression of Islet1 in hindlimb progenitors (Yang et al, 2006) suggests that it might be involved in establishing hindlimb-specific characters.…”

Section: Research Articlementioning

confidence: 99%

Islet1 regulates establishment of the posterior hindlimb field upstream of the Hand2-Shh morphoregulatory gene network in mouse embryos

et al. 2012

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SUMMARYHow divergent genetic systems regulate a common pathway during the development of two serial structures, forelimbs and hindlimbs, is not well understood. Specifically, HAND2 has been shown to regulate Shh directly to initiate its expression in the posterior margin of the limb mesenchyme. Although the Hand2-Shh morphoregulatory system operates in both the forelimb and hindlimb bud, a recent analysis suggested that its upstream regulation is different in the forelimb and hindlimb bud. A combination of all four Hox9 genes is required for Hand2 expression in the forelimb-forming region; however, it remains elusive what genetic system regulates the Hand2-Shh pathway in the hindlimb-forming region. By conditional inactivation of Islet1 in the hindlimb-forming region using the Hoxb6Cre transgene, we show that Islet1 is required for establishing the posterior hindlimb field, but not the forelimb field, upstream of the Hand2-Shh pathway. Inactivation of Islet1 caused the loss of posterior structures in the distal and proximal regions, specifically in the hindlimb. We found that Hand2 expression was downregulated in the hindlimb field and that Shh expression was severely impaired in the hindlimb bud. In the Hoxb6Cre; Islet1 mutant pelvis, the proximal element that is formed in a Shh-independent manner, displayed complementary defects in comparison with Pitx1 -/-hindlimbs. This suggests that Islet1 and Pitx1 function in parallel during girdle development in hindlimbs, which is in contrast with the known requirement for Tbx5 in girdle development in forelimbs. Our studies have identified a role for Islet1 in hindlimb-specific development and have revealed Islet1 functions in two distinct processes: regulation upstream of the Hand2-Shh pathway and contributions to girdle development.

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Divergent transcriptional activities determine limb identity

Cited by 54 publications

References 42 publications

Pitx1 is necessary for normal initiation of hindlimb outgrowth through regulation of Tbx4 expression and shapes hindlimb morphologies via targeted growth control

Pitx1 is necessary for normal initiation of hindlimb outgrowth through regulation of Tbx4 expression and shapes hindlimb morphologies via targeted growth control

Islet1-mediated activation of the β-catenin pathway is necessary for hindlimb initiation in mice

Islet1 regulates establishment of the posterior hindlimb field upstream of the Hand2-Shh morphoregulatory gene network in mouse embryos

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