Van Maldergem syndrome: further characterisation and evidence for neuronal migration abnormalities and autosomal recessive inheritance

Mansour, Sahar; Swinkels, Marielle; Terhal, Paulien A; Wilson, Louise C.; Rich, Philip; Maldergem, Lionel Van; Zwijnenburg, Petra J.G.; Hall, Christine; Robertson, Stephen P.; Newbury‐Ecob, Ruth

doi:10.1038/ejhg.2012.57

Cited by 44 publications

(59 citation statements)

References 13 publications

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“…We have previously reported that in Fat4 and Dchs1 mouse mutants the lumbar vertebrae are malformed, which may be consistent with the vertebral defects reported in humans (Mao et al, 2011;Mansour et al, 2012). The vertebrae in P0 Fat4 and Dchs1 mutants are also wider, raising the possibility that Fat-PCP alters the relative dimensions of the vertebrae during early development.…”

Section: Fat4supporting

confidence: 73%

“…Vertebral development involves complex signalling interactions that must be regulated both temporally and spatially to first specify the somites from the presomitic mesoderm in a regular manner and then to specify the somite into its various somitic cell lineages, including chondrocytes, muscle and dermis (Maroto et al, 2012). Here, we have added another signalling pathway to this network, namely the Fat4-Dchs1 signalling pathway, which is essential for vertebral development in mice and humans (our data; Mansour et al, 2012). In Fat4 and Dchs1 mutants, the vertebrae are narrower along the dorsoventral and anterior-posterior axes.…”

Section: Discussionmentioning

confidence: 99%

“…Gene inactivation of either Fat4 or Dchs1 in mice results in a wide spectrum of phenotypes ranging from branching and cystic defects in the kidney, altered neuronal proliferation and migration, to a change in sternum shape (Saburi et al, 2008(Saburi et al, , 2012Mao et al, 2011Mao et al, , 2015Mao et al, , 2016Zakaria et al, 2014;Bagherie-Lachidan et al, 2015;Badouel et al, 2015). FAT4 and DCHS1 are also essential in humans, and compound mutations result in Van Maldergem syndrome, which is characterised, in part, by intellectual disability and altered craniofacial development (Cappello et al, 2013); in some individuals vertebral defects have also been reported (Mansour et al, 2012). Mutation in FAT4 has also been shown to be responsible in a subset of Hennekam syndrome patients (Alders et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae

et al. 2016

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The protocadherins Fat4 and Dchs1 act as a receptor-ligand pair to regulate many developmental processes in mice and humans, including development of the vertebrae. Based on conservation of function between Drosophila and mammals, Fat4-Dchs1 signalling has been proposed to regulate planar cell polarity (PCP) and activity of the Hippo effectors Yap and Taz, which regulate cell proliferation, survival and differentiation. There is strong evidence for Fat regulation of PCP in mammals but the link with the Hippo pathway is unclear. In Fat4 −/− and Dchs1 −/− mice, many vertebrae are split along the midline and fused across the anterior-posterior axis, suggesting that these defects might arise due to altered cell polarity and/or changes in cell proliferation/differentiation. We show that the somite and sclerotome are specified appropriately, the transcriptional network that drives early chondrogenesis is intact, and that cell polarity within the sclerotome is unperturbed. We find that the key defect in Fat4 and Dchs1 mutant mice is decreased proliferation in the early sclerotome. This results in fewer chondrogenic cells within the developing vertebral body, which fail to condense appropriately along the midline. Analysis of Fat4;Yap and Fat4;Taz double mutants, and expression of their transcriptional target Ctgf, indicates that Fat4-Dchs1 regulates vertebral development independently of Yap and Taz. Thus, we have identified a new pathway crucial for the development of the vertebrae and our data indicate that novel mechanisms of Fat4-Dchs1 signalling have evolved to control cell proliferation within the developing vertebrae.

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Section: Fat4supporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae

et al. 2016

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“…Genetic studies are also needed to understand the precise contribution of progenitor-regulating genes that have altered expression in Fat4 mutants. Determining how Fat4 and Dchs1/2 control Six2-dependent progenitor differentiation/renewal will provide insights into how progenitor self-renewal is controlled, and may explain the renal hypoplasia observed in patients that harbour mutations in FAT4 and DCHS1 (Cappello et al, 2013;Mansour et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Stromal Fat4 acts non-autonomously with Dachsous1/2 to restrict the nephron progenitor pool

et al. 2015

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Regulation of the balance between progenitor self-renewal and differentiation is crucial to development. In the mammalian kidney, reciprocal signalling between three lineages (stromal, mesenchymal and ureteric) ensures correct nephron progenitor self-renewal and differentiation. Loss of either the atypical cadherin FAT4 or its ligand Dachsous 1 (DCHS1) results in expansion of the mesenchymal nephron progenitor pool, called the condensing mesenchyme (CM). This has been proposed to be due to misregulation of the Hippo kinase pathway transcriptional co-activator YAP. Here, we use tissuespecific deletions to prove that FAT4 acts non-autonomously in the renal stroma to control nephron progenitors. We show that loss of Yap from the CM in Fat4-null mice does not reduce the expanded CM, indicating that FAT4 regulates the CM independently of YAP. Analysis of Six2 −/− ;Fat4 −/− double mutants demonstrates that excess progenitors in Fat4 mutants are dependent on Six2, a crucial regulator of nephron progenitor self-renewal. Electron microscopy reveals that cell organisation is disrupted in Fat4 mutants. Gene expression analysis demonstrates that the expression of Notch and FGF pathway components are altered in Fat4 mutants. Finally, we show that Dchs1, and its paralogue Dchs2, function in a partially redundant fashion to regulate the number of nephron progenitors. Our data support a model in which FAT4 in the stroma binds to DCHS1/2 in the mouse CM to restrict progenitor self-renewal.

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“…Requirements for DCHS1 and FAT4 in humans have been revealed by the linkage of mutations in these genes to Van Maldergem syndrome (Cappello et al, 2013). Mice mutant for Dchs1 or Fat4 have smaller kidneys, with fewer ureteric branches and a modest accumulation of small cysts (Mao et al, 2011;Saburi et al, 2008); hypoplastic kidneys have also been reported in Van Maldergem patients (Mansour et al, 2012). Differences between murine wild-type and Dchs1 or Fat4 mutant kidneys appear as early as embryonic day (E) 11.5, when the growth and branching of the UB in mutants lags behind that in wild-type embryos (Mao et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

A Fat4-Dchs1 signal between stromal and cap mesenchyme cells influences nephrogenesis and ureteric bud branching

2015

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Formation of the kidney requires reciprocal signaling among the ureteric tubules, cap mesenchyme and surrounding stromal mesenchyme to orchestrate complex morphogenetic events. The protocadherin Fat4 influences signaling from stromal to cap mesenchyme cells to regulate their differentiation into nephrons. Here, we characterize the role of a putative binding partner of Fat4, the protocadherin Dchs1. Mutation of Dchs1 in mice leads to increased numbers of cap mesenchyme cells, which are abnormally arranged around the ureteric bud tips, and impairment of nephron morphogenesis. Mutation of Dchs1 also reduces branching of the ureteric bud and impairs differentiation of ureteric bud tip cells into trunk cells. Genetically, Dchs1 is required specifically within cap mesenchyme cells. The similarity of Dchs1 phenotypes to stromal-less kidneys and to those of Fat4 mutants implicates Dchs1 in Fat4-dependent stroma-to-cap mesenchyme signaling. Antibody staining of genetic mosaics reveals that Dchs1 protein localization is polarized within cap mesenchyme cells, where it accumulates at the interface with stromal cells, implying that it interacts directly with a stromal protein. Our observations identify a role for Fat4 and Dchs1 in signaling between cell layers, implicate Dchs1 as a Fat4 receptor for stromal signaling that is essential for kidney development, and establish that vertebrate Dchs1 can be molecularly polarized in vivo.

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Van Maldergem syndrome: further characterisation and evidence for neuronal migration abnormalities and autosomal recessive inheritance

Cited by 44 publications

References 13 publications

Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae

Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae

Stromal Fat4 acts non-autonomously with Dachsous1/2 to restrict the nephron progenitor pool

A Fat4-Dchs1 signal between stromal and cap mesenchyme cells influences nephrogenesis and ureteric bud branching

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