An Allelic Series at the PDGFαR Locus Indicates Unequal Contributions of Distinct Signaling Pathways During Development

Klinghoffer, Richard A.; Hamilton, Tim; Hoch, Renée V.; Soriano, Philippe

doi:10.1016/s1534-5807(01)00103-4

Cited by 174 publications

(257 citation statements)

References 63 publications

Supporting

Mentioning

249

Contrasting

Order By: Relevance

“…The present study and that of Klinghoffer et al (2002) demonstrate OPC and oligodendrocyte formation in the absence of PDGFR␣ and formally raise the possibility that PDGFR␣ expression neither identifies all OPCs nor is obligate for OPC development. However, studies to date have not ruled out at least transient expression of PDGFR␣ in all OPC pools, and the contribution of "non-PDGFR␣"-expressing cells to oligodendrocyte formation remains unresolved.…”

Section: Opc Origins and Pdgfr␣supporting

confidence: 58%

“…Substitution studies in mice also demonstrate that the signaling domains of distinct PDGF receptors are qualitatively different. The signaling domain of PDGFR␣ cannot replace that of PDGFR␤ in development (Klinghoffer et al, 2001), and the signaling domains from FGFR1 or Drosophila Tor cannot replace that of PDGFR␣, although it can be replaced by PDGFR␤ (Klinghoffer et al, 2002;Hamilton et al, 2003). These results thus contrast with studies in Drosophila, in which the signaling domains of distinct RTKs can be functionally substituted during development (Dossenbach et al, 2001) and suggest that RTK signaling systems have gained both specificity and complexity with tissue specialization during metazoan evolution.…”

Section: Pdgfr␣ Signaling: Combinatorial Pathwaysmentioning

confidence: 84%

See 1 more Smart Citation

PDGF α-Receptor Signal Strength Controls an RTK Rheostat That Integrates Phosphoinositol 3′-Kinase and Phospholipase Cγ Pathways during Oligodendrocyte Maturation

McKinnon¹,

Waldron²,

Kiel³

2005

J. Neurosci.

View full text Add to dashboard Cite

Receptors with tyrosine kinase activity (RTKs) control tissue growth and development in metazoans. How they generate cell-specific responses remains essentially unknown; one model proposes that distinct RTKs activate different second-messenger pathways, whereas a second proposes that all RTKs deliver a generic "go" signal to these pathways that is uniquely interpreted by downstream, cell-specific response competence factors. We examine pathway activation and pathway-specific responses downstream of PDGF␣ receptors, whose expression in the developing CNS identifies oligodendrocyte progenitor cells (OPCs) and whose activation controls OPC proliferation, migration, survival, and maturation. PDGFR␣-null mice die in utero, and OPCs that emerge before their demise have migration and proliferation defects and rapidly differentiate into postmitotic oligodendrocytes in vitro. OPCs from hemizygous mice also undergo precocious differentiation, indicating a role for PDGFR␣ gene dosage in timing OPC maturation. The rescue of PDGFR␣-null OPCs with PDGFR␣ transgenes revealed specific roles for the phosphatidylinositol 3-kinase (PI3K) and phospholipase C␥ (PLC␥) pathways and a distinct ligand concentration dependence. Activation of the PI3K pathway is required for PDGFR␣-induced migration, whereas activation of both PI3K and PLC␥ are required for PDGFR␣-induced proliferation. For proliferation, PI3K activation is required at low ligand concentration, whereas PLC␥ is required at high signal strength. Dose-response studies further demonstrate that PDGFR␣ activates PI3K at low ligand concentrations, whereas PLC␥ is activated at high signal strength. Thus, PDGFR␣ signaling acts like a rheostat rather than generic ON switch, with signal strength dictating pathway activation during OPC maturation.

show abstract

Section: Opc Origins and Pdgfr␣supporting

confidence: 58%

Section: Pdgfr␣ Signaling: Combinatorial Pathwaysmentioning

confidence: 84%

PDGF α-Receptor Signal Strength Controls an RTK Rheostat That Integrates Phosphoinositol 3′-Kinase and Phospholipase Cγ Pathways during Oligodendrocyte Maturation

McKinnon¹,

Waldron²,

Kiel³

2005

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…2 C-E). To determine whether the loss of PDGFRα in primary cilia attenuated PDGF-driven intracellular signaling, we measured the activation of PDGFRα and the induction of Akt phosphorylation, one of the effectors of PDGF signaling (38). Control osteoblasts stimulated with PDGF ligand [PDGF-AA] robustly activated PDGFRα and induced Akt phosphorylation, but Ift20:Wnt1-Cre osteoblasts did not ( Fig.…”

Section: Disruption Of Ift20 In Neural Crest Cells Results In Craniofmentioning

confidence: 99%

Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development

Noda¹,

Kitami²,

Kitami

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The primary cilium is a cellular organelle that coordinates signaling pathways critical for cell proliferation, differentiation, survival, and homeostasis. Intraflagellar transport (IFT) plays a pivotal role in assembling primary cilia. Disruption and/or dysfunction of IFT components can cause multiple diseases, including skeletal dysplasia. However, the mechanism by which IFT regulates skeletogenesis remains elusive. Here, we show that a neural crest-specific deletion of intraflagellar transport 20 (Ift20) in mice compromises ciliogenesis and intracellular transport of collagen, which leads to osteopenia in the facial region. Whereas platelet-derived growth factor receptor alpha (PDGFRα) was present on the surface of primary cilia in wildtype osteoblasts, disruption of Ift20 down-regulated PDGFRα production, which caused suppression of PDGF-Akt signaling, resulting in decreased osteogenic proliferation and increased cell death. Although osteogenic differentiation in cranial neural crest (CNC)-derived cells occurred normally in Ift20-mutant cells, the process of mineralization was severely attenuated due to delayed secretion of type I collagen. In control osteoblasts, procollagen was easily transported from the endoplasmic reticulum (ER) to the Golgi apparatus. By contrast, despite having similar levels of collagen type 1 alpha 1 (Col1a1) expression, Ift20 mutants did not secrete procollagen because of dysfunctional ER-to-Golgi trafficking. These data suggest that in the multipotent stem cells of CNCs, IFT20 is indispensable for regulating not only ciliogenesis but also collagen intracellular trafficking. Our study introduces a unique perspective on the canonical and noncanonical functions of IFT20 in craniofacial skeletal development.cranial neural crest cells | intracellular trafficking | intraflagellar transport | PDGF signaling | primary cilia

show abstract

“…To date, studies have been reported of several receptors using knock-in mice in which the cytoplasmic tyrosine(s) of a receptor has been replaced with phenylalanine(s) (26)(27)(28)(29)(30). However, it is rare that the substitution of a single tyrosine of a receptor causes the same phenotype as the null mutant mice.…”

Section: Discussionmentioning

confidence: 99%

Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice

Sakurai

Ohgimoto²,

Kataoka³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

286

250

View full text Add to dashboard Cite

Flk-1 (human counterpart, KDR) tyrosine kinase, which is one of the two VEGF receptors, is crucial for vascular development. Recently, we showed that, among tyrosine residues of KDR, tyrosine residues 1175 (Y1175, corresponding to Y1173 in murine Flk-1) and Y1214 (Y1212 in Flk-1) are autophosphorylated in response to VEGF, and that Y1175 is important for VEGF-dependent phospholipase C␥͞PKC͞mitogen-activated protein kinase activation leading to DNA synthesis in cultured endothelial cells. However, the importance of these tyrosine residues in Flk-1͞KDR in vivo is not yet known. To examine the role of these Flk-1 tyrosine residues in vivo, we generated knock-in mice substituting Y1173 and Y1212 of the Flk-1 gene with phenylalanine, respectively. As a result, Flk-1 1173F homozygous mice died between embryonic days 8.5 and 9.5 without any organized blood vessels or yolk sac blood islands, and hematopoietic progenitors were severely reduced, similar to the case of Flk-1 null mice. In contrast, Flk-1 1212F homozygous mice were viable and fertile. These results suggest that the signaling via Y1173 of Flk-1 is essential for endothelial and hematopoietic development during embryogenesis.Flk-1͞KDR ͉ single tyrosine-phenylalanine mutation ͉ tyrosine kinase receptor V EGF is essential for many angiogenic processes both in normal and pathological conditions (1, 2). VEGF binds two tyrosine kinase receptors, Flt-1 (also known as VEGF receptor 1) (3, 4) and Flk-1 (also known as VEGF receptor 2, KDR as human counterpart) (5-7) with high affinity. Flt-1-and Flk-1-deficient mice both die in utero between embryonic days (E) 8.5 and E9.5 but have different phenotypes. Flt-1-deficient embryos showed an overgrowth of endothelial cells and disorganization of blood vessels (8). Moreover, Flt-1 tyrosine kinase-deficient mice showed normal vascular development (9), suggesting that the Flt-1 extracellular domain acts as a negative regulator of VEGF, and that Flt-1 tyrosine kinase is not necessary for vasculogenesis during development. On the other hand, Flk-1-deficient mice lack both mature endothelial and hematopoietic cells, indicating that Flk-1 is crucial for vascular development (10).Ligand binding to Flk-1͞KDR induces autophosphorylation of Flk-1͞KDR intracellular tyrosine residues and activates several signaling pathways, leading to cell proliferation, survival, migration, and permeability (11). Recently, we have shown that tyrosine residues 1175 (Y1175) and Y1214, but not Y801, on KDR are highly autophosphorylated in response to VEGF, and that Y1175 is crucial for VEGF-dependent cell proliferation via the phospholipase C␥ (PLC␥)͞PKC͞mitogen-activated protein kinase (MAPK) pathway in cultured endothelial cells (12). However, the importance of these tyrosine residues in Flk-1͞KDR in vivo remains to be elucidated.To develop a pharmaceutical drug(s) that efficiently suppresses angiogenesis in diseases such as cancer, it is important to identify the tyrosine residue(s) that is involved in the critical signaling pathway via Flk-1͞KDR for ...

show abstract

An Allelic Series at the PDGFαR Locus Indicates Unequal Contributions of Distinct Signaling Pathways During Development

Cited by 174 publications

References 63 publications

PDGF α-Receptor Signal Strength Controls an RTK Rheostat That Integrates Phosphoinositol 3′-Kinase and Phospholipase Cγ Pathways during Oligodendrocyte Maturation

PDGF α-Receptor Signal Strength Controls an RTK Rheostat That Integrates Phosphoinositol 3′-Kinase and Phospholipase Cγ Pathways during Oligodendrocyte Maturation

Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development

Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice

Contact Info

Product

Resources

About