Disruption of PDGFRα-initiated PI3K activation and migration of somite derivatives leads to spina bifida

Pickett, Elizabeth; Olsen, Gregory S.; Tallquist, Michelle D.

doi:10.1242/dev.013763

Cited by 44 publications

(44 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PDGFRα signals through PI3 kinase to AKT activation Experiments in mice have suggested that one of the major signalling pathways downstream of PDGFRα is activation of PI3 kinase (Klinghoffer et al, 2002;Pickett et al, 2008). In previous experiments, we showed that PIP3 signalling is necessary for the directionality of the movement response of mesoderm cells during gastrulation in the chick embryo (Leslie et al, 2007).…”

Section: Research Articlementioning

confidence: 79%

PDGF signalling controls the migration of mesoderm cells during chick gastrulation by regulating N-cadherin expression

2008

View full text Add to dashboard Cite

In the early chick embryo, Pdgfa is expressed in the epiblast,outlining the migration route that mesoderm cells expressing the receptor, Pdgfrα, follow to form somites. Both expression of a dominant-negative PDGFRα and depletion of endogenous PDGFRαligands through injection of PDGFRα-Fc fragments, inhibit the migration of mesoderm cells after their ingression through the primitive streak. siRNA-mediated downregulation of Pdgfa expression in the epiblast on one side of the streak strongly blocks the migration of mesoderm cells into that side. Beads soaked in PDGFA elicit a directional attractive movement response in mesoderm cells, showing that PDGFA can provide directional information. Surprisingly, however, PDGF signalling is also required for directional movement towards other attractants, such as FGF4. PDGF signalling controls N-cadherin expression on mesoderm cells, which is required for efficient migration. PDGF signalling activates the PI3 kinase signalling pathway in vivo and activation of this pathway is required for proper N-cadherin expression.

show abstract

Section: Research Articlementioning

confidence: 79%

PDGF signalling controls the migration of mesoderm cells during chick gastrulation by regulating N-cadherin expression

2008

View full text Add to dashboard Cite

show abstract

“…Conversely, an additional study examining the role of PDGFRa signaling in somite-derived structures revealed a cell migration defect in the somite-derived dorsal mesenchyme but no apoptotic or proliferation abnormalities in Pdgfra PI3K/PI3K neural arches or sclerotome (Pickett et al 2008), pointing to regional differences in the response of embryonic tissues to PI3K-mediated PDGFRa signaling.…”

Section: Discussionmentioning

confidence: 93%

PI3K-mediated PDGFRα signaling regulates survival and proliferation in skeletal development through p53-dependent intracellular pathways

Fantauzzo

Soriano

2014

Genes Dev.

View full text Add to dashboard Cite

Previous studies have identified phosphatidylinositol 3-kinase (PI3K) as the main downstream effector of PDGFRα signaling during murine skeletal development. Autophosphorylation mutant knock-in embryos in which PDGFRα is unable to bind PI3K (PdgfraPI3K/PI3K) exhibit skeletal defects affecting the palatal shelves, shoulder girdle, vertebrae, and sternum. To identify proteins phosphorylated by Akt downstream from PI3K-mediated PDGFRα signaling, we immunoprecipitated Akt phosphorylation substrates from PDGF-AA-treated primary mouse embryonic palatal mesenchyme (MEPM) lysates and analyzed the peptides by nanoliquid chromatography coupled to tandem mass spectrometry (nano-LC-MS/MS). Our analysis generated a list of 56 proteins, including 10 that regulate cell survival and proliferation. We demonstrate that MEPM cell survival is impaired in the presence of a PI3K inhibitor and that PdgfraPI3K/PI3K-derived MEPMs do not proliferate in response to PDGF-AA treatment. Several of the identified Akt phosphorylation targets, including Ybox1, mediate cell survival through regulation of p53. We show that Ybox1 binds both the Trp53 promoter and the p53 protein and that expression of Trp53 is significantly decreased upon PDGF-AA treatment in MEPMs. Finally, we demonstrate that introduction of a Trp53-null allele attenuates the vertebral defects found in PdgfraPI3K/PI3K neonates. Our findings identify p53 as a novel effector downstream from PI3K-engaged PDGFRα signaling that regulates survival and proliferation during skeletal development in vivo.

show abstract

“…Finally, paxillin or FAK ablation in mice is embryonic lethal (Sieg et al, 2000;Hagel et al, 2002), and recent studies in vivo have shown that deletion of the PDGF receptor in mice or paxillin in Xenopus laevis resulted in impaired cell polarity and directional cell migration (Iioka et al, 2007;Pickett et al, 2008), giving rise to the developmental defect spina bifida and abnormal convergent extension, respectively (Iioka et al, 2007;Prasad and Montell, 2007;Llense and Martin-Blanco, 2008;Pickett et al, 2008). Furthermore, Rho family GTPase signaling, as well as PAK activity, was significantly disrupted in the absence of the PDGF receptor (Pickett et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Paxillin-Kinase-Linker Tyrosine Phosphorylation Regulates Directional Cell Migration

Deakin

Turner

2009

MBoC

View full text Add to dashboard Cite

Directed cell migration requires the coordination of growth factor and cell adhesion signaling and is of fundamental importance during embryonic development, wound repair, and pathological conditions such as tumor metastasis. Herein, we demonstrate that the ArfGAP, paxillin-kinase-linker (PKL/GIT2), is tyrosine phosphorylated in response to plateletderived growth factor (PDGF) stimulation, in an adhesion dependent manner and is necessary for directed cell migration. Using a combination of pharmacological inhibitors, knockout cells and kinase mutants, FAK, and Src family kinases were shown to mediate PDGF-dependent PKL tyrosine phosphorylation. In fibroblasts, expression of a PKL mutant lacking the principal tyrosine phosphorylation sites resulted in loss of wound-induced cell polarization as well as directional migration. PKL phosphorylation was necessary for PDGF-stimulated PKL binding to the focal adhesion protein paxillin and expression of paxillin or PKL mutants defective in their respective binding motifs recapitulated the polarization defects. RNA interference or expression of phosphorylation mutants of PKL resulted in disregulation of PDGF-stimulated Rac1 and PAK activities, reduction of Cdc42 and Erk signaling, as well as mislocalization of ␤PIX. Together these studies position PKL as an integral component of growth factor and cell adhesion cross-talk signaling, controlling the development of front-rear cell polarity and directional cell migration. INTRODUCTIONDirected cell migration requires front-rear cell polarization and plays a fundamental role during development, the innate immune response and wound repair as well as in tumor cell metastasis (Lauffenburger and Horwitz, 1996;Ridley et al., 2003). Chemoattractant (e.g., growth factor) gradients in combination with extracellular matrix (ECM) cues provide the external stimuli necessary to establish and maintain the asymmetric shape of polarized cells, through the regulation of integrin-based cell adhesion and reorganization of the actin and microtubule cytoskeleton (Etienne-Manneville and Hall, 2002, 2008;Ridley et al., 2003). For example, coordinated signaling between PDGF receptors and integrins in fibroblasts and vascular cells facilitates directional cell migration during organogenesis, blood vessel patterning, and wound healing (Heldin and Westermark, 1999;Duchek et al., 2001;Nagel et al., 2004;Wood et al., 2006).The nonreceptor tyrosine kinase FAK, in combination with the Src family kinases (SFKs), has emerged as a central effector, mediating cross-talk between activated growth factor receptor tyrosine kinases such as PDGF and engaged integrins Juliano, 2002). In turn, FAK/Src regulates focal adhesion turnover and cytoskeletal remodeling (Webb et al., 2004;Zaidel-Bar et al., 2007), through tyrosine phosphorylation of various key focal adhesion adapter proteins such as paxillin and p130Cas (Thomas and Brugge, 1997;Schlaepfer et al., 1999;Brown and Turner, 2004), as well as critical regulators of Rho GTPase signaling including the guanine nucleoti...

show abstract

Disruption of PDGFRα-initiated PI3K activation and migration of somite derivatives leads to spina bifida

Cited by 44 publications

References 84 publications

PDGF signalling controls the migration of mesoderm cells during chick gastrulation by regulating N-cadherin expression

PDGF signalling controls the migration of mesoderm cells during chick gastrulation by regulating N-cadherin expression

PI3K-mediated PDGFRα signaling regulates survival and proliferation in skeletal development through p53-dependent intracellular pathways

Paxillin-Kinase-Linker Tyrosine Phosphorylation Regulates Directional Cell Migration

Contact Info

Product

Resources

About