Over-expression of Grhl2 causes spina bifida in the Axial defects mutant mouse

Brouns, Madeleine R.; Castro, Sandra C. P. De; Terwindt‐Rouwenhorst, E. A. W.; Massa, Valentina; Hekking, Johan W.M.; Hirst, Caroline S.; Savery, Dawn; Munts, Chantal; Partridge, Darren; Lamers, W. H.; Köhler, Susanne; Straaten, Henny W. van; Copp, Andrew J.; Greene, Nicholas D. E.

doi:10.1093/hmg/ddr031

Cited by 50 publications

(72 citation statements)

References 30 publications

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“…It is interesting to note that the spina bifida in Sdc4 lacZ/lacZ ;Vangl2 Lp/+ mice is reminiscent of that observed in the curly tail mutant, which carries a hypomorphic mutation of the transcription factor grainyhead-like 3 ( Grhl3 ) (Brouns et al, 2011; Gustavsson et al, 2007). In curly tail , there is a decrease in cell proliferation specifically in the hindgut (Copp et al, 1988), with a consequent increase in ventral curvature causing mechanical obstruction of PNP closure that results in spina bifida (Brook et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity

Escobedo¹,

Contreras²,

Muñoz³

et al. 2013

Development

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Syndecan 4 (Sdc4) is a cell-surface heparan sulfate proteoglycan (HSPG) that regulates gastrulation, neural tube closure and directed neural crest migration in Xenopus development. To determine whether Sdc4 participates in Wnt/PCP signaling during mouse development, we evaluated a possible interaction between a null mutation of Sdc4 and the loop-tail allele of Vangl2. Sdc4 is expressed in multiple tissues, but particularly in the non-neural ectoderm, hindgut and otic vesicles. Sdc4;Vangl2Lp compound mutant mice have defective spinal neural tube closure, disrupted orientation of the stereocilia bundles in the cochlea and delayed wound healing, demonstrating a strong genetic interaction. In Xenopus, co-injection of suboptimal amounts of Sdc4 and Vangl2 morpholinos resulted in a significantly greater proportion of embryos with defective neural tube closure than each individual morpholino alone. To probe the mechanism of this interaction, we overexpressed or knocked down Vangl2 function in HEK293 cells. The Sdc4 and Vangl2 proteins colocalize, and Vangl2, particularly the Vangl2Lp mutant form, diminishes Sdc4 protein levels. Conversely, Vangl2 knockdown enhances Sdc4 protein levels. Overall HSPG steady-state levels were regulated by Vangl2, suggesting a molecular mechanism for the genetic interaction in which Vangl2Lp/+ enhances the Sdc4-null phenotype. This could be mediated via heparan sulfate residues, as Vangl2Lp/+ embryos fail to initiate neural tube closure and develop craniorachischisis (usually seen only in Vangl2Lp/Lp) when cultured in the presence of chlorate, a sulfation inhibitor. These results demonstrate that Sdc4 can participate in the Wnt/PCP pathway, unveiling its importance during neural tube closure in mammalian embryos.

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Section: Discussionmentioning

confidence: 99%

Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity

Escobedo¹,

Contreras²,

Muñoz³

et al. 2013

Development

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“…The causative mutations are not known but both result in misregulation of Grhl expression. Axd mutants exhibit increased Grhl2 expression, and NT closure can be restored by decreasing the level of Grhl2 (Brouns et al, 2011). Ct mutants show decreased expression of Grhl3, and NT closure can be rescued by Grhl3 overexpression (Gustavsson et al, 2007).…”

Section: Transcriptional Regulation Of Neural Tube Fusionmentioning

confidence: 99%

Mechanisms of tissue fusion during development

2012

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Tissue fusion events during embryonic development are crucial for the correct formation and function of many organs and tissues, including the heart, neural tube, eyes, face and body wall. During tissue fusion, two opposing tissue components approach one another and integrate to form a continuous tissue; disruption of this process leads to a variety of human birth defects. Genetic studies, together with recent advances in the ability to culture developing tissues, have greatly enriched our knowledge of the mechanisms involved in tissue fusion. This review aims to bring together what is currently known about tissue fusion in several developing mammalian organs and highlights some of the questions that remain to be addressed.

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“…Grhl2 is one of three mouse homologs of Drosophila Grainyhead (Wilanowski et al, 2002) and is expressed in diverse embryonic epithelial tissues during development (Wilanowski et al, 2002;Auden et al, 2006). Grhl2 and its paralog Grhl3 play essential roles in neural tube closure in mice (Rifat et al, 2010;Werth et al, 2010;Brouns et al, 2011;Pyrgaki et al, 2011). All three members regulate the expression of epithelial junctional genes (Yu et al, 2006;Wilanowski et al, 2008;Werth et al, 2010;Pyrgaki et al, 2011;Senga et al, 2012;Varma et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

A Grhl2-dependent gene network controls trophoblast branching morphogenesis

et al. 2015

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Healthy placental development is essential for reproductive success; failure of the feto-maternal interface results in pre-eclampsia and intrauterine growth retardation. We found that grainyhead-like 2 (GRHL2), a CP2-type transcription factor, is highly expressed in chorionic trophoblast cells, including basal chorionic trophoblast (BCT) cells located at the chorioallantoic interface in murine placentas. Placentas from Grhl2-deficient mouse embryos displayed defects in BCT cell polarity and basement membrane integrity at the chorioallantoic interface, as well as a severe disruption of labyrinth branching morphogenesis. Selective Grhl2 inactivation only in epiblast-derived cells rescued all placental defects but phenocopied intraembryonic defects observed in global Grhl2 deficiency, implying the importance of Grhl2 activity in trophectoderm-derived cells. ChIP-seq identified 5282 GRHL2 binding sites in placental tissue. By integrating these data with placental gene expression profiles, we identified direct and indirect Grhl2 targets and found a marked enrichment of GRHL2 binding adjacent to genes downregulated in Grhl2(-/-) placentas, which encoded known regulators of placental development and epithelial morphogenesis. These genes included that encoding the serine protease inhibitor Kunitz type 1 (Spint1), which regulates BCT cell integrity and labyrinth formation. In human placenta, we found that human orthologs of murine GRHL2 and its targets displayed co-regulation and were expressed in trophoblast cells in a similar domain as in mouse placenta. Our data indicate that a conserved Grhl2-coordinated gene network controls trophoblast branching morphogenesis, thereby facilitating development of the site of feto-maternal exchange. This might have implications for syndromes related to placental dysfunction

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Over-expression of Grhl2 causes spina bifida in the Axial defects mutant mouse

Cited by 50 publications

References 30 publications

Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity

Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity

Mechanisms of tissue fusion during development

A Grhl2-dependent gene network controls trophoblast branching morphogenesis

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