Mutations in IRX5 impair craniofacial development and germ cell migration via SDF1

Bonnard, Carine; Strobl, Anna; Shboul, Mohammad; Lee, Hane; Merriman, Barry; Nelson, Stanley F.; Ababneh, Osama H.; Uz, Elif; Güran, Tülay; Kayserili, Hülya; Hamamy, Hanan; Reversade, Bruno

doi:10.1038/ng.2259

Cited by 72 publications

(78 citation statements)

References 29 publications

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“…An attractive model then is that Irx proteins compete with or modify Sox9a activity at the R2 enhancer, thus dampening Sox9a-mediated activation of col2a1a . As Irx5 and Trps1 form a transcriptional complex with Irx3 in Xenopus (Bonnard et al, 2012), it will be interesting to test whether a similar complex involving Irx5a, Trps1, and Irx7 represses the expression of col2a1a , acana , and other chondrocyte matrix genes at the hyoid joint.…”

Section: Resultsmentioning

confidence: 99%

Iroquois Proteins Promote Skeletal Joint Formation by Maintaining Chondrocytes in an Immature State

et al. 2015

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Summary An early event in skeletal joint development is the specification of articular chondrocytes at the joint surface. Articular chondrocytes are distinct in producing lower levels of cartilage matrix and not being replaced by bone, yet how they acquire these properties remains poorly understood. Here, we show that two members of the Iroquois transcriptional repressor family, Irx7 and Irx5a, function to block chondrocyte maturation at the developing hyoid joint of zebrafish. These Irx factors suppress the production of cartilage matrix at the joint in part by preventing the activation of a col2a1a enhancer by Sox9a. Further, both zebrafish Irx7 and mouse IRX1 are able to repress cartilage matrix production in a murine chondrogenic cell line. Iroquois proteins may therefore have a conserved role in keeping chondrocytes in an immature state, with the lower levels of cartilage matrix produced by these immature cells contributing to joint flexibility.

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Section: Resultsmentioning

confidence: 99%

Iroquois Proteins Promote Skeletal Joint Formation by Maintaining Chondrocytes in an Immature State

et al. 2015

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“…It also includes the calcium binding protein 4, which has an important role in synaptic function in photoreceptor cells [54] and the iroquois-class homeodomain protein (IRX5). IRX5 is a transcription factor that is involved in cone cell differentiation and retinal, craniofacial and gonad development [55, 56]. The transcription factor HES4 was also up-regulated in the brains of sexually mature males.…”

Section: Discussionmentioning

confidence: 99%

Changes in the gene expression profiles of the brains of male European eels (Anguilla anguilla) during sexual maturation

et al. 2014

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BackgroundThe vertebrate brain plays a critical role in the regulation of sexual maturation and reproduction by integrating environmental information with developmental and endocrine status. The European eel Anguilla anguilla is an important species in which to better understand the neuroendocrine factors that control reproduction because it is an endangered species, has a complex life cycle that includes two extreme long distance migrations with both freshwater and seawater stages and because it occupies a key position within the teleost phylogeny. At present, mature eels have never been caught in the wild and little is known about most aspects of reproduction in A. anguilla. The goal of this study was to identify genes that may be involved in sexual maturation in experimentally matured eels. For this, we used microarrays to compare the gene expression profiles of sexually mature to immature males.ResultsUsing a false discovery rate of 0.05, a total of 1,497 differentially expressed genes were identified. Of this set, 991 were expressed at higher levels in brains (forebrain and midbrain) of mature males while 506 were expressed at lower levels relative to brains of immature males. The set of up-regulated genes includes genes involved in neuroendocrine processes, cell-cell signaling, neurogenesis and development. Interestingly, while genes involved in immune system function were down-regulated in the brains of mature males, changes in the expression levels of several receptors and channels were observed suggesting that some rewiring is occurring in the brain at sexual maturity.ConclusionsThis study shows that the brains of eels undergo major changes at the molecular level at sexual maturity that may include re-organization at the cellular level. Here, we have defined a set of genes that help to understand the molecular mechanisms controlling reproduction in eels. Some of these genes have previously described functions while many others have roles that have yet to be characterized in a reproductive context. Since most of the genes examined here have orthologs in other vertebrates, the results of this study will contribute to the body of knowledge concerning reproduction in vertebrates as well as to an improved understanding of eel biology.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-799) contains supplementary material, which is available to authorized users.

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“…Recessive IRX5 mutations result in cardiac structural and electrophysiological defects as part of Hamamy syndrome (Bonnard et al, 2012). It is not clear whether the human IRX5 mutations lead to simple loss of IRX5 function or whether they cause a broader dominant effect, but the disparity between mutations in IRX5 and the mouse Irx5 loss of function might also be explained by differences in the function of Irx5 in mouse and human.…”

Section: Discussionmentioning

confidence: 99%

Cooperative and antagonistic roles for Irx3 and Irx5 in cardiac morphogenesis and postnatal physiology

et al. 2012

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SUMMARYThe Iroquois homeobox (Irx) homeodomain transcription factors are important for several aspects of embryonic development. In the developing heart, individual Irx genes are important for certain postnatal cardiac functions, including cardiac repolarization (Irx5) and rapid ventricular conduction (Irx3). Irx genes are expressed in dynamic and partially overlapping patterns in the developing heart. Here we show in mice that Irx3 and Irx5 have redundant function in the endocardium to regulate atrioventricular canal morphogenesis and outflow tract formation. Our data suggest that direct transcriptional repression of Bmp10 by Irx3 and Irx5 in the endocardium is required for ventricular septation. A postnatal deletion of Irx3 and Irx5 in the myocardium leads to prolongation of atrioventricular conduction, due in part to activation of expression of the Na + channel protein Nav1.5. Surprisingly, combined postnatal loss of Irx3 and Irx5 results in a restoration of the repolarization gradient that is altered in Irx5 mutant hearts, suggesting that postnatal Irx3 activity can be repressed by Irx5. Our results have uncovered complex genetic interactions between Irx3 and Irx5 in embryonic cardiac development and postnatal physiology.

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Mutations in IRX5 impair craniofacial development and germ cell migration via SDF1

Cited by 72 publications

References 29 publications

Iroquois Proteins Promote Skeletal Joint Formation by Maintaining Chondrocytes in an Immature State

Iroquois Proteins Promote Skeletal Joint Formation by Maintaining Chondrocytes in an Immature State

Changes in the gene expression profiles of the brains of male European eels (Anguilla anguilla) during sexual maturation

Cooperative and antagonistic roles for Irx3 and Irx5 in cardiac morphogenesis and postnatal physiology

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