Function and regulation of Alx4 in limb development: Complex genetic interactions with Gli3 and Shh

Kuijper, Sanne; Feitsma, Harma; Sheth, Rushikesh; Korving, Jeroen; Reijnen, Mark; Meijlink, Frits

doi:10.1016/j.ydbio.2005.06.017

Cited by 54 publications

(64 citation statements)

References 55 publications

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“…This suggests that in certain cellular contexts, Gli3 binding to a regulatory region may indirectly promote anterior expression, perhaps by blocking the action of some other repressive function. However, analysis of one of these genes, Alx4, has identified a regulatory region that recapitulate Gli3-dependent expression and this region shows no GBRs in our data set (Kuijper et al 2005).…”

Section: ;Gli3mentioning

confidence: 64%

A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb

Vokes¹,

Ji²,

Wong³

et al. 2008

Genes Dev.

280

423

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Sonic hedgehog (Shh) signals via Gli transcription factors to direct digit number and identity in the vertebrate limb. We characterized the Gli-dependent cis-regulatory network through a combination of whole-genome chromatin immunoprecipitation (ChIP)-on-chip and transcriptional profiling of the developing mouse limb. These analyses identified ∼5000 high-quality Gli3-binding sites, including all known Gli-dependent enhancers. Discrete binding regions exhibit a higher-order clustering, highlighting the complexity of cis-regulatory interactions. Further, Gli3 binds inertly to previously identified neural-specific Gli enhancers, demonstrating the accessibility of their cis-regulatory elements. Intersection of DNA binding data with gene expression profiles predicted 205 putative limb target genes. A subset of putative cis-regulatory regions were analyzed in transgenic embryos, establishing Blimp1 as a direct Gli target and identifying Gli activator signaling in a direct, long-range regulation of the BMP antagonist Gremlin. In contrast, a long-range silencer cassette downstream from Hand2 likely mediates Gli3 repression in the anterior limb. These studies provide the first comprehensive characterization of the transcriptional output of a Shh-patterning process in the mammalian embryo and a framework for elaborating regulatory networks in the developing limb.[Keywords: Sonic hedgehog; limb; morphogen; gli; cis-regulatory network] Supplemental material is available at http://www.genesdev.org. The vertebrate limb is one of the best studied models of how morphogen signaling elaborates a complex pattern (for review, see McGlinn and Tabin 2006). Shh secreted by a discrete posterior organizing center, the zone of polarizing activity (ZPA), is thought to act as a long-range, concentration-dependent signal that regulates both the number and identity of digits that arise from the distal mesenchyme of the developing limb bud. Both the concentration and time of Shh signaling are critical, and growth couples with morphogen activity to give the final digit pattern (Yang et al. 1997;Harfe et al. 2004;Towers et al. 2008;Zhu et al. 2008). Shh actions are mediated through the Gli transcriptional effector family (Gli1-3). Of these, Gli3 appears to play a crucial role in regulating digit number; loss of Gli3 repressor leads to polydactyly and suppresses the loss of digits (2-5) observed in Shh mutants (Litingtung et al. 2002;te Welscher et al. 2002b). Interactions between the limb mesenchyme and the apical ectodermal ridge (AER) are critical for digit development.The Shh pathway is thought to maintain the limb outgrowth-promoting role of AER produced FGFs through the regulation of a BMP antagonist, Gremlin (Zuniga et al. 1999;Khokha et al. 2003). In turn, AER signaling is essential for maintaining Shh expression (Laufer et al. 1994;Niswander et al. 1994). Genetic analyses have suggested that Shh-mediated loss of Gli3 repressor activity underlies the Shh → Gremlin → AER circuit, but whether this is a direct action of Gli repressor has no...

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Section: ;Gli3mentioning

confidence: 64%

A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb

Vokes¹,

Ji²,

Wong³

et al. 2008

Genes Dev.

280

423

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“…Mutations in WNT5A are causing the dominant Human Robinow syndrome, characterized by short stature, limb shortening, genital hypoplasia and craniofacial abnormalities [35]. ALX4 loss of function mutations cause polydactily in the mouse, through disregulation of the sonic hedgehog (SHH) signaling factor [36], [37]. Moreover, the ALX4 protein has been shown to bind proteins from the HOXA (HOXA11 and HOXA3) and HOXC (HOXC4 and HOXC5) clusters [38].…”

Section: Resultsmentioning

confidence: 99%

Selection Signatures in Worldwide Sheep Populations

Fariello¹,

et al. 2014

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The diversity of populations in domestic species offers great opportunities to study genome response to selection. The recently published Sheep HapMap dataset is a great example of characterization of the world wide genetic diversity in sheep. In this study, we re-analyzed the Sheep HapMap dataset to identify selection signatures in worldwide sheep populations. Compared to previous analyses, we made use of statistical methods that (i) take account of the hierarchical structure of sheep populations, (ii) make use of linkage disequilibrium information and (iii) focus specifically on either recent or older selection signatures. We show that this allows pinpointing several new selection signatures in the sheep genome and distinguishing those related to modern breeding objectives and to earlier post-domestication constraints. The newly identified regions, together with the ones previously identified, reveal the extensive genome response to selection on morphology, color and adaptation to new environments.

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“…Analysis of polydactyly mutations showed that Shh transcription is negatively regulated by several genes including Fgf, Gli3, and aristaless-like 4 (Alx4). Deficiency in Gli3, which encodes a zinc finger protein that acts as a transcription factor, leads to the extra toes (Xt) mutation, and the Alx4 is considered to be linked to the mouse mutant Strong's luxoid (Lst) Qu et al, 1998;Kuijper et al, 2005;Panman et al, 2005). During limb bud development, Alx4 becomes critical for repression of anterior ectopic Shh expression (Qu et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Multiple abnormalities due to a nonsense mutation in the Alx4 gene

Chen

Chen²,

Zhou³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Patterning of the limb anterior-posterior axes depends on several signals that derive from the three signaling centers of the limb bud. These signals interact to constitute a complex and ordered network that critically contributes to the development of limb buds. Preaxial polydactyly in mouse is predominantly caused by ectopic expression of the zone of polarizing activity or Sonic hedgehog in the anterior region of the limb bud. In this study, we describe an N-ethyl-N-nitrosourea-induced polydactylous mouse ( Alx4 m1Yzcm ) with an extra digit on the anterior aspect of one or two hinddigits. The mutation was mapped to chromosome 2, between markers D2Mit45 and D2Mit184. The Alx4 gene was identified as a potential candidate gene in this location. Sequence analysis of the Alx4 gene for polydactylous heterozygotes revealed an A/T transversion mutation that resulted in substitution of a lysine codon with a stop (nonsense) codon at position 145. Alx4 m1Yzcm homozygous mice exhibited multiple abnormalities, including extensive preaxial polydactyly of all four limbs (up to seven digits) and the formation of omphalocele.

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Function and regulation of Alx4 in limb development: Complex genetic interactions with Gli3 and Shh

Cited by 54 publications

References 55 publications

A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb

A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb

Selection Signatures in Worldwide Sheep Populations

Multiple abnormalities due to a nonsense mutation in the Alx4 gene

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