A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis

Guo, Caiwei; Sun, Ye; Zhou, Bin; Adam, Rosalyn M.; Li, Xiaokun; Pu, William T.; Morrow, Bernice E.; Moon, Anne M.; Li, Xue

doi:10.1172/jci44630

Cited by 128 publications

(119 citation statements)

References 70 publications

(123 reference statements)

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“…Eya1 is required for normal development of a number of organs, including the kidney (4), inner ear (32,33), pituitary gland (5), and cardiovascular system (6). Amount these organs, kidney is particularly sensitive to levels of Eya1 activity, making kidney size as an attractive indicator of (20 g/ml), and the Flag/Eya1 protein level was chased in a period of 6 h and quantified using ImageJ based on signal density and a protein loading control (GAPDH).…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, it is required for development of and is capable of inducing the ectopic Drosophila eye (1)(2)(3). The function of mammalian Eya family proteins, however, expands beyond organogenesis (4)(5)(6), from tumorigenesis (7-10) to tissue remodeling (11,12) to innate immunity (13). The underlying mechanism of Eya1 pleotropic functions remains to be fully defined.…”

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confidence: 99%

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The Canonical Wnt Signal Restricts the Glycogen Synthase Kinase 3/Fbw7-Dependent Ubiquitination and Degradation of Eya1 Phosphatase

Sun

2014

Molecular and Cellular Biology

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Haploinsufficiency of Eya1 causes the branchio-oto-renal (BOR) syndrome, and abnormally high levels of Eya1 are linked to breast cancer progression and poor prognosis. Therefore, regulation of Eya1 activity is key to its tissue-specific functions and oncogenic activities. Here, we show that Eya1 is posttranslationally modified by ubiquitin and that its ubiquitination level is selflimited to prevent premature degradation. Eya1 has an evolutionarily conserved CDC4 phosphodegron (CPD) signal, a target site of glycogen synthase kinase 3 (GSK3) kinase and Fbw7 ubiquitin ligase, which is required for Eya1 ubiquitination. Genetic deletion of Fbw7 and pharmacological inhibition of GSK3 significantly decrease Eya1 ubiquitination. Conversely, activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and the canonical Wnt signal suppresses Eya1 ubiquitination. Compound Eya1 ؉/؊ ; Wnt9b ؉/؊ mutants exhibit an increased penetrance of renal defect, indicating that they function in the same genetic pathway in vivo. Together, these findings reveal that the canonical Wnt and PI3K/Akt signal pathways restrain the GSK3/Fbw7-dependent Eya1 ubiquitination, and they further suggest that dysregulation of this novel axis contributes to tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

The Canonical Wnt Signal Restricts the Glycogen Synthase Kinase 3/Fbw7-Dependent Ubiquitination and Degradation of Eya1 Phosphatase

Sun

2014

Molecular and Cellular Biology

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“…The expression analysis was expanded to transcription factors known to be involved in the morphogenesis of the pouches and formation of these organs, the Pax1 and Fgf8 genes (Dietrich and Gruss, 1995;Wallin et al, 1996;Su et al, 2001;Guo et al, 2011;Frank et al, 2002). In vitro and in vivo assays were performed as described in the previous section (schematic representation, Figure 3A).…”

Section: Notch Signalling Inhibition Promotes the Reduction Of Foxn1 mentioning

confidence: 99%

Notch and Hedgehog in the thymus/parathyroid common primordium: Crosstalk in organ formation

Figueiredo

Silva

Santos

et al. 2016

Developmental Biology

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Neves, Notch and Hedgehog in the thymus/parathyroid common primordium: Crosstalk in organ f o r m a t i o n , Developmental Biology, http://dx.doi.org/10. 1016/j.ydbio.2016.08.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe avian thymus and parathyroids (T/PT) common primordium derives from the endoderm of the third and fourth pharyngeal pouches (3/4PP). The molecular mechanisms that govern T/PT development are not fully understood. Here we study the effects of Notch and Hedgehog (Hh) signalling modulation during common primordium development using in vitro, in vivo and in ovo approaches. The impairment of Notch activity reduced Foxn1/thymus-fated and Gcm2/Pth/parathyroid-fated domains in the 3/4PP and further compromised the development of the parathyroid glands. When Hh signalling was abolished, we observed a reduction in the Gata3/Gcm2-and Lfng-expression domains at the median/anterior and median/posterior territories of the pouches, respectively. In contrast, the Foxn1 expression- This study offers novel evidence on the role of Notch signalling in T/PT common primordium development, in an Hh-dependent manner.

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“…Tbx1 gene regulates the expression of ascidian Ciona intestinalis ortholog of Ebf, COE, in the cardiopharyngeal progenitors, which produce the heart precursors and the branchiomeric muscles (Razy-Krajka et al 2014;Wang et al 2013) (Table 1). Moreover, both Tbx1 and Ebf2 are necessary for regulation of the myogenic factor MyoD in the branchiomeric head muscles of a vertebrate (Green and Vetter 2011;Grifone et al 2008;Guo et al 2011). Thus, we predict that RA may regulate cEbf2 expression in the muscle progenitor cells of the PAs through activation of Tbx1 gene, but this needs to be experimentally proved, and this conserved action is crucial for pharyngeal muscle development in vertebrates and tunicates.…”

Section: Discussionmentioning

confidence: 99%

The effect of RA on the chick Ebf1-3 genes expression in somites and pharyngeal arches

et al. 2014

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Expression of chick early B cell factor 1-3 (cEbf1-3) genes in regions of high retinoic acid (RA) activity, such as somites and pharyngeal arches (PAs), and regulation of other EBF members by RA raise the possibility that the internal cue RA may regulate cEbf1-3 expression in these tissues. To check this possibility, RA gain and loss of function experiments were conducted. Ectopic expression of RA led to up-regulation of cEbf2, 3 but did not change cEbf1 expression in somites. Expectedly, inhibition of RA by disulfiram resulted in downregulation of cEbf2, 3, but did not change cEbf1 expression in somites. The same RA gain and loss of function experiments did not change cEbf1-3 expression in PAs. However, ectopic expression of RA in the cranial neural tube before migration of neural crest cells downregulated cEbf1, 3 and up-regulated cEbf2 expression in the PAs. The same experiment, but with application of disulfiram, resulted in downregulation of cEbf2, but did not alter the expression of the other two genes. We conclude that the three cEbf genes act differently in response to RA signals in somitic mesoderm. cEbf1 may be not RA dependant in somites; however, the other two cEbf genes positively respond to RA signalling in somites. Additionally, only the migratory cEbf-expressing cells into the PAs are affected by RA signals.

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A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis

Cited by 128 publications

References 70 publications

The Canonical Wnt Signal Restricts the Glycogen Synthase Kinase 3/Fbw7-Dependent Ubiquitination and Degradation of Eya1 Phosphatase

The Canonical Wnt Signal Restricts the Glycogen Synthase Kinase 3/Fbw7-Dependent Ubiquitination and Degradation of Eya1 Phosphatase

Notch and Hedgehog in the thymus/parathyroid common primordium: Crosstalk in organ formation

The effect of RA on the chick Ebf1-3 genes expression in somites and pharyngeal arches

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