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Philippe Soriano

Publications and source records attributed to Philippe Soriano.

16 recordsLinked to original sources
PubMed2005

PDGFR-alpha signaling is critical for tooth cusp and palate morphogenesis.

Platelet-derived growth factor receptor alpha (PDGFR-alpha) and PDGF ligands are key regulators for embryonic development. Although Pdgfralpha is spatially expressed in the cranial neural crest (CNC)-derived odontogenic mesenchyme, mice deficient for Pdgfralpha are embryonic lethal, making it impossible to investigate the functional significance of PDGF signaling in regulating the fate of CNC cells during tooth morphogenesis. Taking advantage of the kidney capsule assay, we investigated the biological function of PDGF signaling in regulating tooth morphogenesis. Pdgfralpha and Pdgfa are specifically and consistently expressed in the CNC-derived odontogenic mesenchyme and the dental epithelium, respectively, throughout all stages of tooth development, suggesting a paracrine function of PDGF signaling in regulating tooth morphogenesis. Highly concentrated expression patterns of Pdgfralpha and Pdgfa are associated with the developing dental cusp, suggesting possible functional importance of PDGF signaling in regulating cusp formation. Loss of the Pdgfralpha gene does not affect proper odontoblasts proliferation and differentiation in the CNC-derived odontogenic mesenchyme but perturbs the formation of extracellular matrix and the organization of odontoblast cells at the forming cusp area, resulting in dental cusp growth defect. Pdgfralpha-/- mice have complete cleft palate. We show that the cleft palate in Pdgfralpha mutant mice results from an extracellular matrix defect within the CNC-derived palatal mesenchyme. The midline epithelium of the mutant palatal shelf remains functionally competent to mediate palatal fusion once the palatal shelves are placed in close contact in vitro. Collectively, our data suggests that PDGFRalpha and PDGFA are critical regulators for the continued epithelial-mesenchymal interaction during tooth and palate morphogenesis. Disruption of PDGFRalpha signaling disturbs the growth of dental cusp and interferes with the critical extension of palatal shelf during craniofacial development.

Animals↗
PubMed2005

Ephrin signaling in vivo: look both ways.

Eph receptors and ephrins have captured the interest of the developmental biology community in recent years for their pleiotropic functions during embryogenesis. Loss-of-function studies using various animal models have demonstrated the involvement of Ephs and ephrins in many aspects of embryogenesis including segmentation, neural crest cells migration, angiogenesis, and axon guidance. An essential property of this signaling pathway is the ability of both Ephs and ephrins to behave as receptors or ligands and their consequent cell autonomous and nonautonomous mode of action. While many reports did not discriminate between Eph autonomous signaling (forward) and ephrin autonomous signaling (reverse), recent genetic and in vivo studies have shown that both forward and reverse signaling play important roles during embryogenesis.

Animals↗
PubMed2004

A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling.

PDGF-C is a member of the platelet-derived growth factor (PDGF) family, which signals through PDGF receptor (PDGFR) alphaalpha and alphabeta dimers. Here we show that Pdgfc(-/-) mice die in the perinatal period owing to feeding and respiratory difficulties associated with a complete cleft of the secondary palate. This phenotype was less severe than that of Pdgfra(-/-) embryos. Pdgfc(-/-) Pdgfa(-/-) embryos developed a cleft face, subepidermal blistering, deficiency of renal cortex mesenchyme, spina bifida and skeletal and vascular defects. Complete loss of function of both ligands, therefore, phenocopied the loss of PDGFR-alpha function, suggesting that both PDGF-A and PDGF-C signal through PDGFR-alpha to regulate the development of craniofacial structures, the neural tube and mesodermal organs. Our results also show that PDGF-C signaling is a new pathway in palatogenesis, different from, and independent of, those previously implicated.

Abnormalities, Multiple↗
PubMed2004

In vivo convergence of BMP and MAPK signaling pathways: impact of differential Smad1 phosphorylation on development and homeostasis.

Integration of diverse signaling pathways is essential in development and homeostasis for cells to interpret context-dependent cues. BMP and MAPK signaling converge on Smads, resulting in differential phosphorylation. To understand the physiological significance of this observation, we have generated Smad1 mutant mice carrying mutations that prevent phosphorylation of either the C-terminal motif required for BMP downstream transcriptional activation (Smad1(C) mutation) or of the MAPK motifs in the linker region (Smad1(L) mutation). Smad1(C/C) mutants recapitulate many Smad1(-/-) phenotypes, including defective allantois formation and the lack of primordial germ cells (PGC), but also show phenotypes that are both more severe (head and branchial arches) and less severe (allantois growth) than the null. Smad1(L/L) mutants survive embryogenesis but exhibit defects in gastric epithelial homeostasis correlated with changes in cell contacts, actin cytoskeleton remodeling, and nuclear beta-catenin accumulation. In addition, formation of PGCs is impaired in Smad1(L/L) mutants, but restored by allelic complementation in Smad1(C/L) compound mutants. These results underscore the need to tightly balance BMP and MAPK signaling pathways through Smad1.

Animals↗
PubMed2004

Ephrin-B1 forward and reverse signaling are required during mouse development.

Eph receptors and ephrin ligands are key players in many developmental processes including embryo patterning, angiogenesis, and axon guidance. Eph/ephrin interactions lead to the generation of a bidirectional signal, in which both the Eph receptors and the ephrins activate downstream signaling cascades simultaneously. To understand the role of ephrin-B1 and the importance of ephrin-B1-induced reverse signaling during embryonic development, we have generated mouse lines carrying mutations in the efnb1 gene. Complete ablation of ephrin-B1 resulted in perinatal lethality associated with a range of phenotypes, including defects in neural crest cell (NCC)-derived tissues, incomplete body wall closure, and abnormal skeletal patterning. Conditional deletion of ephrin-B1 demonstrated that ephrin-B1 acts autonomously in NCCs, and controls their migration. Last, a mutation in the PDZ binding domain indicated that ephrin-B1-induced reverse signaling is required in NCCs. Our results demonstrate that ephrin-B1 acts both as a ligand and as a receptor in a tissue-specific manner during embryogenesis.

Animals↗
PubMed2004

Identification and validation of PDGF transcriptional targets by microarray-coupled gene-trap mutagenesis.

We developed a versatile, high-throughput genetic screening strategy by coupling gene mutagenesis and expression profiling technologies. Using a retroviral gene-trap vector optimized for efficient mutagenesis and cloning, we randomly disrupted genes in mouse embryonic stem (ES) cells and amplified them to construct a cDNA microarray. With this gene-trap array, we show that transcriptional target genes of platelet-derived growth factor (PDGF) can be efficiently and reliably identified in physiologically relevant cells and are immediately accessible to genetic studies to determine their in vivo roles and relative contributions to PDGF-regulated developmental processes. The same platform can be used to search for genes of specific biological relevance in a broad array of experimental settings, providing a fast track from gene identification to functional validation.

Animals↗
PubMed2004

The knockout mouse project.

Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain.

Alleles↗
PubMed2003

Additive effects of PDGF receptor beta signaling pathways in vascular smooth muscle cell development.

The platelet-derived growth factor beta receptor (PDGFRbeta) is known to activate many molecules involved in signal transduction and has been a paradigm for receptor tyrosine kinase signaling for many years. We have sought to determine the role of individual signaling components downstream of this receptor in vivo by analyzing an allelic series of tyrosine-phenylalanine mutations that prevent binding of specific signal transduction components. Here we show that the incidence of vascular smooth muscle cells/pericytes (v/p), a PDGFRbeta-dependent cell type, can be correlated to the amount of receptor expressed and the number of activated signal transduction pathways. A decrease in either receptor expression levels or disruption of multiple downstream signaling pathways lead to a significant reduction in v/p. Conversely, loss of RasGAP binding leads to an increase in this same cell population, implicating a potential role for this effector in attenuating the PDGFRbeta signal. The combined in vivo and biochemical data suggest that the summation of pathways associated with the PDGFRbeta signal transduction determines the expansion of developing v/p cells.

Alleles↗
PubMed2003

Cryptic boundaries in roof plate and choroid plexus identified by intersectional gene activation.

The hindbrain roof plate and choroid plexus are essential organizing centers for inducing dorsal neuron fates and sustaining neuron function. To map the formation of these structures, we developed a broadly applicable, high resolution, recombinase-based method for mapping the fate of cells originating from coordinates defined by intersecting combinations of expressed genes. Using this method, we show that distinct regions of hindbrain roof plate originate from discrete subdomains of rhombencephalic neuroectoderm expressing Wnt1; that choroid plexus, a secretory epithelium important for patterning later-formed hindbrain structures and maintaining neuron function, derives from the same embryonic primordium as the hindbrain roof plate; and that, unlike the floor plate, these dorsal organizing centers develop in a patterned, segmental manner, built from lineage-restricted compartments. Our data suggest that the roof plate and choroid plexus may be formed of functional units that are capable of differentially organizing the generation of distinct neuronal cell types at different axial levels.

Alkaline Phosphatase↗
PubMed2003

Evolutionary divergence of platelet-derived growth factor alpha receptor signaling mechanisms.

Receptor tyrosine kinases (RTKs) direct diverse cellular and developmental responses by stimulating a relatively small number of overlapping signaling pathways. Specificity may be determined by RTK expression patterns or by differential activation of individual signaling pathways. To address this issue we generated knock-in mice in which the extracellular domain of the mouse platelet-derived growth factor alpha receptor (PDGFalphaR) is fused to the cytosolic domain of Drosophila Torso (alpha(Tor)) or the mouse fibroblast growth factor receptor 1 (alpha(FR)). alpha(Tor) homozygous embryos exhibit significant rescue of neural crest and angiogenesis defects normally found in PDGFalphaR-null embryos yet fail to rescue skeletal or extraembryonic defects. This phenotype was associated with the ability of alpha(Tor) to stimulate the mitogen-activated protein (MAP) kinase pathway to near wild-type levels but failure to completely activate other pathways, such as phosphatidylinositol (PI) 3-kinase. The alpha(FR) chimeric receptor fails to rescue any aspect of the PDGFalphaR-null phenotype. Instead, alpha(FR) expression leads to a gain-of-function phenotype highlighted by ectopic bone development. The alpha(FR) phenotype was associated with a failure to limit MAP kinase signaling and to engage significant PI3-kinase response. These results suggest that precise regulation of divergent downstream signaling pathways is critical for specification of RTK function.

Animals↗
PubMed2003

Cell autonomous requirement for PDGFRalpha in populations of cranial and cardiac neural crest cells.

Cardiac and cephalic neural crest cells (NCCs) are essential components of the craniofacial and aortic arch mesenchyme. Genetic disruption of the platelet-derived growth factor receptor alpha (PDGFRalpha) results in defects in multiple tissues in the mouse, including neural crest derivatives contributing to the frontonasal process and the aortic arch. Using chimeric analysis, we show that loss of the receptor in NCCs renders them inefficient at contributing to the cranial mesenchyme. Conditional gene ablation in NCCs results in neonatal lethality because of aortic arch defects and a severely cleft palate. The conotruncal defects are first observed at E11.5 and are consistent with aberrant NCC development in the third, fourth and sixth branchial arches, while the bone malformations present in the frontonasal process and skull coincide with defects of NCCs from the first to third branchial arches. Changes in cell proliferation, migration, or survival were not observed in PDGFRalpha NCC conditional embryos, suggesting that the PDGFRalpha may play a role in a later stage of NCC development. Our results demonstrate that the PDGFRalpha plays an essential, cell-autonomous role in the development of cardiac and cephalic NCCs and provides a model for the study of aberrant NCC development.

Animals↗
PubMed2003

Roles of PDGF in animal development.

Recent advances in genetic manipulation have greatly expanded our understanding of cellular responses to platelet-derived growth factors (PDGFs) during animal development. In addition to driving mesenchymal proliferation, PDGFs have been shown to direct the migration, differentiation and function of a variety of specialized mesenchymal and migratory cell types, both during development and in the adult animal. Furthermore, the availability of genomic sequence data has facilitated the identification of novel PDGF and PDGF receptor (PDGFR) family members in C. elegans, Drosophila, Xenopus, zebrafish and mouse. Early data from these different systems suggest that some functions of PDGFs have been evolutionarily conserved.

Animals↗
PubMed2002

[Beta]IV-spectrin regulates sodium channel clustering through ankyrin-G at axon initial segments and nodes of Ranvier.

beta-Spectrin and ankyrin are major components of the membrane cytoskeleton. We have generated mice carrying a null mutation in the betaIV-spectrin gene using gene trapping in embryonic stem cells. Mice homozygous for the mutation exhibit tremors and contraction of hindlimbs. betaIV-spectrin expression is mostly restricted to neurons, where it colocalizes with and binds to ankyrin-G at axon initial segments (AISs) and nodes of Ranvier (NR). In betaIV-spectrin-null neurons, neither ankyrin-G nor voltage-gated sodium channels (VGSC) are correctly clustered at these sites, suggesting that impaired action potential caused by mislocalization of VGSC leads to the phenotype. Conversely, in ankyrin-G-null neurons, betaIV-spectrin is not localized to these sites. These results indicate that betaIV-spectrin and ankyrin-G mutually stabilize the membrane protein cluster and the linked membrane cytoskeleton at AIS and NR.

Animals↗
PubMed2002

An allelic series at the PDGFalphaR locus indicates unequal contributions of distinct signaling pathways during development.

A central issue in signal transduction is the physiological contribution of different growth factor-initiated signaling pathways. We have generated knockin mice harboring mutations in the PDGFalpha receptor (PDGFalphaR) that selectively eliminate its capacity to activate PI3 kinase (alpha(PI3K)) or Src family kinases (alpha(Src)). The alpha(PI3K) mutation leads to neonatal lethality due to impaired signaling in many cell types, but the alpha(Src) mutation only affects oligodendrocyte development. A third knockin line containing mutations that eliminate multiple docking sites does not increase the severity of the alpha(PI3K) mutation. However, embryos with mutations in the PI3K binding sites of both PDGFRs (alpha and beta) recapitulate the PDGFalphaR null phenotype. Our results indicate that PI3K has a predominant role in PDGFalphaR signaling in vivo and that RTK-activated signaling pathways execute both specific and overlapping functions during mammalian development.

Alleles↗
PubMed2002

Overlapping and unique roles for C-terminal binding protein 1 (CtBP1) and CtBP2 during mouse development.

The C-terminal binding protein (CtBP) family of proteins has been linked to multiple biological processes through their association with numerous transcription factors. We generated mice harboring mutations in both Ctbp1 and Ctbp2 to address the in vivo function of CtBPs during vertebrate development. Ctbp1 mutant mice are small but viable and fertile, whereas Ctbp2-null mice show defects in axial patterning and die by E10.5 due to aberrant extraembryonic development. Mice harboring various combinations of Ctbp1 and Ctbp2 mutant alleles exhibit dosage-sensitive defects in a wide range of developmental processes. The strong genetic interaction, as well as transcription assays with CtBP-deficient cells, indicates that CtBPs have overlapping roles in regulating gene expression. We suggest that the observed phenotypes reflect the large number of transcription factors whose activities are compromised in the absence of CtBP.

Abnormalities, Multiple↗