Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development

Cappello, Silvia; Gray, Mary Jane; Badouel, Caroline; Lange, Simona; Einsiedler, Melanie; Srour, Myriam; Chitayat, David; Hamdan, Fadi F.; Jenkins, Zandra A.; Morgan, Tim; Preitner, Nadia; Uster, Tami; Thomas, Jasmin; Shannon, Patrick; Morrison, V. Anne; Donato, Nataliya Di; Maldergem, Lionel Van; Neuhann, Teresa; Newbury‐Ecob, Ruth; Swinkells, Marielle; Terhal, Paulien A; Wilson, Louise C.; Zwijnenburg, Petra J.G.; Sutherland-Smith, Andrew J.; Black, Michael A.; Markie, David; Michaud, Jacques L.; Simpson, Michael A.; Mansour, Sahar; McNeill, Helen; Götz, Magdalena; Robertson, Stephen P.

doi:10.1038/ng.2765

Cited by 225 publications

(291 citation statements)

References 75 publications

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“…In the developing cortex, Yap is expressed in radial precursors and not in differentiated neurons (Cappello et al, 2013). Immunostaining of Yap in Fat4 and/or Fat1 mutants revealed an expansion of Yappositive cells that follows the expansion of radial precursors (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies suggest a role for the Yorkie homolog Yap (Yap1) in controlling neural progenitor maintenance downstream of Fat4 (Van Hateren et al, 2011;Cappello et al, 2013). In the developing cortex, Yap is expressed in radial precursors and not in differentiated neurons (Cappello et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Although structure/function analyses suggest that the Drosophila growth regulatory domain is not conserved in Fat4 (Matakatsu and Blair, 2012;Zhao et al, 2013;Bossuyt et al, 2014), Fat4 restricts the growth of neuronal progenitors in the developing chick neural tube (Van Hateren et al, 2011). Moreover, Fat4 mutations are associated with Van Maldergem syndrome, a recessive multiple malformation syndrome in humans that includes periventricular neuronal heterotopia (Cappello et al, 2013). Fat4 localizes at the subapical domain of neuronal cortical precursors in the mouse, where it regulates the height of the subapical region (Ishiuchi et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development

et al. 2015

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Mammalian brain development requires coordination between neural precursor proliferation, differentiation and cellular organization to create the intricate neuronal networks of the adult brain. Here, we examined the role of the atypical cadherins Fat1 and Fat4 in this process. We show that mutation of Fat1 in mouse embryos causes defects in cranial neural tube closure, accompanied by an increase in the proliferation of cortical precursors and altered apical junctions, with perturbations in apical constriction and actin accumulation. Similarly, knockdown of Fat1 in cortical precursors by in utero electroporation leads to overproliferation of radial glial precursors. Fat1 interacts genetically with the related cadherin Fat4 to regulate these processes. Proteomic analysis reveals that Fat1 and Fat4 bind different sets of actin-regulating and junctional proteins. In vitro data suggest that Fat1 and Fat4 form cis-heterodimers, providing a mechanism for bringing together their diverse interactors. We propose a model in which Fat1 and Fat4 binding coordinates distinct pathways at apical junctions to regulate neural progenitor proliferation, neural tube closure and apical constriction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development

et al. 2015

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“…Fat4 is involved in planar cell polarity signalling, and mutations in human FAT4 and its receptor DCHS1 are associated with Van Maldergem syndrome, which is characterised by abnormal positioning of neurons in the cerebral cortex of patients (Cappello et al, 2013). Knockdown of these proteins in the mouse show they are important in neuroprogenitor cell proliferation, maintenance of the progenitor state and positioning of cells within the proliferative zones of the developing brain.…”

Section: Brn2 Is Upstream Of a Neurogenic Transcriptional Network In mentioning

confidence: 99%

A Brn2–Zic1 axis specifies the neuronal fate of retinoic-acid-treated embryonic stem cells

Urban

Kobi

Ennen

et al. 2015

Journal of Cell Science

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Mouse embryonic stem cells (ESCs) treated with all-trans retinoic acid differentiate into a homogenous population of glutamatergic neurons. Although differentiation is initiated through activation of target genes by the retinoic acid receptors, the downstream transcription factors specifying neuronal fate are less well characterised. Here, we show that the transcription factor Brn2 (also known as Pou3f2) is essential for the neuronal differentiation programme. By integrating results from RNA-seq following Brn2 silencing with results from Brn2 ChIP-seq, we identify a set of Brn2 target genes required for the neurogenic programme. Further integration of Brn2 ChIP-seq data from retinoicacid-treated ESCs and P19 cells with data from ESCs differentiated into neuronal precursors by Fgf2 treatment and that from fibroblasts trans-differentiated into neurons by ectopic Brn2 expression showed that Brn2 occupied a distinct but overlapping set of genomic loci in these differing conditions. However, a set of common binding sites and target genes defined the core of the Brn2-regulated neuronal programme, among which was that encoding the transcription factor Zic1. Small hairpin RNA (shRNA)-mediated silencing of Zic1 prevented ESCs from differentiating into neuronal precursors, thus defining a hierarchical Brn2-Zic1 axis that is essential to specify neural fate in retinoic-acid-treated ESCs.

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“…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%

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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Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development

Cited by 225 publications

References 75 publications

Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development

Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development

A Brn2–Zic1 axis specifies the neuronal fate of retinoic-acid-treated embryonic stem cells

Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae

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