SHH propagates distal limb bud development by enhancing CYP26B1-mediated retinoic acid clearance via AER-FGF signalling

Probst, Simone; Kraemer, Conradin; Demougin, Philippe; Sheth, Rushikesh; Martin, Gail R.; Shiratori, Hidetaka; Hamada, Hiroshi; Iber, Dagmar; Zeller, Rolf; Zúñiga, Aimée

doi:10.1242/dev.063966

Cited by 95 publications

(121 citation statements)

References 55 publications

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“…We cannot, however, exclude another possible explanation of the incomplete rescue: that Meis genes affect Hoxa13 expression via multiple parallel pathways, RA being only one of them. Notably, the fact that the MEIS effect is cell-autonomous, despite acting through a diffusible signal (RA) is consistent with studies showing that RA degradation by CYP26 enzymes has a more determining role than RA diffusion on tissue patterning, very likely due to the different kinetics of the two processes (Hernandez et al, 2007;Probst et al, 2011;White et al, 2007).…”

Section: Meis Genes Control Spatial Distribution Of Hoxa13 Expressionsupporting

confidence: 80%

“…3A, n=0/6). To discard the possibility that additional signals were needed, we also applied beads soaked in the distal signals FGF8 and sonic hedgehog (SHH) (Mariani et al, 2008;Mercader et al, 2000;Probst et al, 2011), but this was again insufficient to prematurely activate Hoxa13 expression at 10 hpi (Fig. 3C,n=0/8).…”

Section: Time Is Also Necessary For Hoxa13 Activationmentioning

confidence: 99%

“…Once Hoxa13 expression starts, the shape of its expression domain therefore reflects the RA signal map in the limb bud. The initial posterior bias of the Hoxa13 domain (Mercader et al, 2009;Nelson et al, 1996;Yokouchi et al, 1991) could be due to at least two non-exclusive possibilities: (1) the fact that SHH, released from the posterior region, enhances CYP26B1-mediated RA clearance (Probst et al, 2011); and (2) transient repression of Hoxa13 by PRC2 in the anterior region of the limb bud, as Ezh2 elimination from the limb leads to anterior expansion of the early Hoxa13 expression domain (Wyngaarden et al, 2011). Finally, Hoxa13-mediated repression of Hoxa11 then establishes exclusive Hoxa13 expression in autopod precursors (Fig.…”

Section: A Dual Mechanism Model Of Limb Pd Patterningmentioning

confidence: 99%

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Diffusible signals and epigenetic timing cooperate in late proximo-distal limb patterning

et al. 2014

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Developing vertebrate limbs initiate proximo-distal patterning by interpreting opposing gradients of diffusible signaling molecules. We report two thresholds of proximo-distal signals in the limb bud: a higher threshold that establishes the upper-arm to forearm transition; and a lower one that positions a later transition from forearm to hand. For this last transition to happen, however, the signal environment seems to be insufficient, and we show that a timing mechanism dependent on histone acetylation status is also necessary. Therefore, as a consequence of the time dependence, the lower signaling threshold remains cryptic until the timing mechanism reveals it. We propose that this timing mechanism prevents the distal transition from happening too early, so that the prospective forearm has enough time to expand and form a properly sized segment. Importantly, the gene expression changes provoked by the first transition further regulate proximo-distal signal distribution, thereby coordinating the positioning of the two thresholds, which ensures robustness. This model is compatible with the most recent genetic analyses and underscores the importance of growth during the time-dependent patterning phase, providing a new mechanistic framework for understanding congenital limb defects.

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Section: Meis Genes Control Spatial Distribution Of Hoxa13 Expressionsupporting

confidence: 80%

Section: Time Is Also Necessary For Hoxa13 Activationmentioning

confidence: 99%

Section: A Dual Mechanism Model Of Limb Pd Patterningmentioning

confidence: 99%

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Diffusible signals and epigenetic timing cooperate in late proximo-distal limb patterning

et al. 2014

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“…This regulation could reflect direct trans-activation by HOX proteins and/or indirect regulation through intermediary molecules. Supporting a contribution from the latter scenario, it was reported that Shh, which is activated by Hox function (Kmita et al 2005), is required for normal Shox2 transcript levels at E10.5 (Probst et al 2011). This downregulation of Shox2 expression is transient, however, as HoxA c/c ; HoxD 2/2 animals show similar Shox2 expression at E11 to wild type, despite having a drastic difference in limb bud morphology ( Figure 5).…”

Section: Resultsmentioning

confidence: 63%

Genetic Interactions Between Shox2 and Hox Genes During the Regional Growth and Development of the Mouse Limb

2014

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The growth and development of the vertebrate limb relies on homeobox genes of the Hox and Shox families, with their independent mutation often giving dose-dependent effects. Here we investigate whether Shox2 and Hox genes function together during mouse limb development by modulating their relative dosage and examining the limb for nonadditive effects on growth. Using double mRNA fluorescence in situ hybridization (FISH) in single embryos, we first show that Shox2 and Hox genes have associated spatial expression dynamics, with Shox2 expression restricted to the proximal limb along with Hoxd9 and Hoxa11 expression, juxtaposing the distal expression of Hoxa13 and Hoxd13. By generating mice with all possible dosage combinations of mutant Shox2 alleles and HoxA/D cluster deletions, we then show that their coordinated proximal limb expression is critical to generate normally proportioned limb segments. These epistatic interactions tune limb length, where Shox2 underexpression enhances, and Shox2 overexpression suppresses, Hox-mutant phenotypes. Disruption of either Shox2 or Hox genes leads to a similar reduction in Runx2 expression in the developing humerus, suggesting their concerted action drives cartilage maturation during normal development. While we furthermore provide evidence that Hox gene function influences Shox2 expression, this regulation is limited in extent and is unlikely on its own to be a major explanation for their genetic interaction. Given the similar effect of human SHOX mutations on regional limb growth, Shox and Hox genes may generally function as genetic interaction partners during the growth and development of the proximal vertebrate limb.T HE vertebrate limb is a valuable model for studying the genetic coordination of a complex developing structure. The proximodistal axis of the limb is composed of discrete segments, the growth and development of which are selectively perturbed when individual, or combinations of, homeobox genes are disrupted. In mice, mutations of the paralogous Hox9 and Hox10 genes result in shortened stylopodal elements (containing the humerus and femur) (FromentalRamain et al. 1996a;Wellik and Capecchi 2003), deletions of Hox11 genes result in truncated zeugopodal elements (radius/ ulna and fibula/tibia) (Davis et al. 1995;Wellik and Capecchi 2003), and disruption of Hox13 genes results in agenesis of the autopod (metacarpals/metatarsals and the digits) (FromentalRamain et al. 1996b). Mutation of short stature homeobox (Shox) genes similarly gives rise to the disproportionate shortening of certain limb regions. In humans, loss of SHOX leads to the truncated zeugopod elements found in people with LeriWeill, Turner, and Langer syndromes (Rao et al. 1997;Belin et al. 1998;Shears et al. 1998;Zinn et al. 2002). While rodents have uniquely lost the Shox gene among mammals (Gianfrancesco et al. 2001), disruption of the widely conserved Shox2 gene results in severely shortened stylopodal elements in mice (Cobb et al. 2006). Thus, Hox and Shox gene perturbations each give ...

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“…Since signaling circuitry involving the AER and underlying mesenchyme has been reported to be inhibited by high levels of RA, which is thought to mimic an exaggerated version of proximal signals (Probst et al, 2011), we investigated whether RING1 activity could be influenced by excess RA signaling. We thus examined whether transient increases in RA signaling at E10.5 could modify the limb defects in Ring1B mutant mice.…”

Section: Ring1 Activity Is Correlated With Regionalizing Signals Of Fmentioning

confidence: 99%

RING1 contributes to early proximal-distal specification of the forelimb bud by restricting Meis2 expression

et al. 2015

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Polycomb group (PcG) proteins play a pivotal role in silencing developmental genes and help to maintain various stem and precursor cells and regulate their differentiation. PcG factors also regulate dynamic and complex regional specification, particularly in mammals, but this activity is mechanistically not well understood. In this study, we focused on proximal-distal (PD) patterning of the mouse forelimb bud to elucidate how PcG factors contribute to a regional specification process that depends on developmental signals. Depletion of the RING1 proteins RING1A (RING1) and RING1B (RNF2), which are essential components of Polycomb repressive complex 1 (PRC1), led to severe defects in forelimb formation along the PD axis. We show that preferential defects in early distal specification in Ring1A/B-deficient forelimb buds accompany failures in the repression of proximal signal circuitry bound by RING1B, including Meis1/2, and the activation of distal signal circuitry in the prospective distal region. Additional deletion of Meis2 induced partial restoration of the distal gene expression and limb formation seen in the Ring1A/B-deficient mice, suggesting a crucial role for RING1-dependent repression of Meis2 and likely also Meis1 for distal specification. We suggest that the RING1-MEIS1/2 axis is regulated by early PD signals and contributes to the initiation or maintenance of the distal signal circuitry.

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SHH propagates distal limb bud development by enhancing CYP26B1-mediated retinoic acid clearance via AER-FGF signalling

Cited by 95 publications

References 55 publications

Diffusible signals and epigenetic timing cooperate in late proximo-distal limb patterning

Diffusible signals and epigenetic timing cooperate in late proximo-distal limb patterning

Genetic Interactions Between Shox2 and Hox Genes During the Regional Growth and Development of the Mouse Limb

RING1 contributes to early proximal-distal specification of the forelimb bud by restricting Meis2 expression

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