Broad mesodermal and endodermal deletion of <i>Nodal</i> at postgastrulation stages results solely in left/right axial defects

Kumar, Amit; Lualdi, Margaret; Lewandoski, Mark; Kuehn, Michael R.

doi:10.1002/dvdy.21665

Cited by 28 publications

(46 citation statements)

References 51 publications

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“…The availability of the Tg(Ttr-cre)10-3Xyfu transgenic mouse line expressing Cre recombinase under the control of regulatory elements of the transthyretin ( Ttr ) gene (Moh et al, 2007), known to be expressed in the VE (Li et al, 2010), in conjunction with our previously validated conditional allele Nodal tm2Mku (Kumar et al, 2008), has allowed us to directly address the role of Nodal in the VE. We find that the absence of Nodal signaling originating from within the VE leads to substantially lower Nodal gene expression within the adjacent wild type epiblast.…”

Section: Introductionmentioning

confidence: 99%

Nodal signaling from the visceral endoderm is required to maintain Nodal gene expression in the epiblast and drive DVE/AVE migration

Kumar

Lualdi

Lyozin

et al. 2015

Developmental Biology

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In the early mouse embryo, a specialized population of extraembryonic visceral endoderm (VE) cells called the anterior VE (AVE) establishes the anterior posterior (AP) axis by restricting gastrulation-inducing signals to the opposite pole. These cells arise at the distal tip of the egg cylinder stage embryo and then asymmetrically migrate to the prospective anterior following the path of an earlier arising and migrating population called the distal VE (DVE). The Nodal-signaling pathway has been shown to have a critical role in the generation of the DVE and AVE and in their migration. The Nodal gene is expressed in both the VE and in the pluripotent epiblast, which gives rise to the germ layers. Previous findings have provided conflicting evidence as to the relative importance of Nodal signaling from the epiblast vs. VE for AP patterning. Here we show that conditional mutagenesis of the Nodal gene specifically within the VE leads to reduced Nodal expression levels in the epiblast and incomplete or failed AVE migration. These results support a required role for VE Nodal to maintain normal levels of expression in the epiblast, and suggest signaling from both VE and epiblast is important for AVE migration.

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Section: Introductionmentioning

confidence: 99%

Nodal signaling from the visceral endoderm is required to maintain Nodal gene expression in the epiblast and drive DVE/AVE migration

Kumar

Lualdi

Lyozin

et al. 2015

Developmental Biology

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“…Nodal genes are expressed in the left lateral plate mesoderm and required for left -right axis specification (Levin et al 1995;Collignon et al 1996;Lowe et al 1996;Yan et al 1999;Lowe et al 2001;Long et al 2003;Kumar et al 2008). Asymmetric activation of the pathway induces asymmetric organ morphogenesis (Yan et al 1999;Bamford et al 2000;Concha et al 2000;Concha et al 2003;Halpern et al 2003;Yashiro et al 2007;Davis et al 2008;de Campos-Baptista et al 2008;Kurpios et al 2008;Bakkers et al 2009;Roussigne et al 2009).…”

Section: Left-right Patterningmentioning

confidence: 99%

Nodal Morphogens

Schier

2009

Cold Spring Harbor Perspectives in Biology

254

290

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Nodal signals belong to the TGF-b superfamily and are essential for the induction of mesoderm and endoderm and the determination of the left-right axis. Nodal signals can act as morphogens-they have concentration-dependent effects and can act at a distance from their source of production. Nodal and its feedback inhibitor Lefty form an activator/inhibitor pair that behaves similarly to postulated reaction-diffusion models of tissue patterning. Nodal morphogen activity is also regulated by microRNAs, convertases, TGF-b signals, coreceptors, and trafficking factors. This article describes how Nodal morphogens pattern embryonic fields and discusses how Nodal morphogen signaling is modulated.

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“…The Nodal gene encodes a ligand of the TGF-b family and is expressed first in the node and subsequently in the left lateral plate mesoderm (LPM), and the transcription factor Pitx2 is later expressed in the left LPM; mutant alleles of each of these genes are embryonic lethal with laterality defects. [29][30][31][32] A majority of proteins associated with human cystic diseases, including the polycystins and nephrocystins, localize to either the axoneme and/or the basal body of primary cilia. 8,33 Similarly, NEK8 localizes to the base of renal cilia and is thus far the only kinase that has been localized to the ciliary axoneme.…”

mentioning

confidence: 99%

Loss of the Ciliary Kinase Nek8 Causes Left-Right Asymmetry Defects

Manning¹,

Sergeev

Heesbeen

et al. 2013

Journal of the American Society of Nephrology

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A missense mutation in mouse Nek8, which encodes a ciliary kinase, produces the juvenile cystic kidneys (jck) model of polycystic kidney disease, but the functions of Nek8 are incompletely understood. Here, we generated a Nek8-null allele and found that homozygous mutant mice die at birth and exhibit randomization of left-right asymmetry, cardiac anomalies, and glomerular kidney cysts. The requirement for Nek8 in left-right patterning is conserved, as knockdown of the zebrafish ortholog caused randomized heart looping. Ciliogenesis was intact in Nek8-deficient embryos and cells, but we observed misexpression of left-sided marker genes early in development, suggesting that nodal ciliary signaling was perturbed. We also generated jck/Nek8 compound heterozygotes; these mutants developed less severe cystic disease than jck homozygotes and provided genetic evidence that the jck allele may encode a gain-of-function protein. Notably, NEK8 and polycystin-2 (PC2) proteins interact, and we found that Nek8 2/2 and Pkd2 2/2 embryonic phenotypes are strikingly similar. Nek8-deficient embryos and cells did express PC2 normally, which localized properly to the cilia. However, similar to cells lacking PC2, NEK8-depleted inner medullary collecting duct cells exhibited a defective response to fluid shear, suggesting that NEK8 may play a role in mediating PC2-dependent signaling.

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Broad mesodermal and endodermal deletion of Nodal at postgastrulation stages results solely in left/right axial defects

Cited by 28 publications

References 51 publications

Nodal signaling from the visceral endoderm is required to maintain Nodal gene expression in the epiblast and drive DVE/AVE migration

Nodal signaling from the visceral endoderm is required to maintain Nodal gene expression in the epiblast and drive DVE/AVE migration

Nodal Morphogens

Loss of the Ciliary Kinase Nek8 Causes Left-Right Asymmetry Defects

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