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

Tallquist MD, French WJ, Soriano P - PLoS Biol. (2003)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Program in Developmental Biology and Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. michelle.tallquist@utsouthwestern.edu

ABSTRACT
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.

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Reduction in V/P Cells in the Thoracic Region of E14.5 EmbryosVentral view of E14.5 wild-type and F7/− littermates with the XlacZ4 mouse marker background. β-Galactosidase-positive nuclei represent v/p cells. Th, thymus.
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pbio.0000052-g004: Reduction in V/P Cells in the Thoracic Region of E14.5 EmbryosVentral view of E14.5 wild-type and F7/− littermates with the XlacZ4 mouse marker background. β-Galactosidase-positive nuclei represent v/p cells. Th, thymus.

Mentions: To determine whether the reduction in v/p was caused by a gradual loss or a developmental defect, we examined pericyte populations in wild-type and mutant embryos. The XlacZ4 mouse marker can be used to identify specific v/p cell populations as early as E12.5. We chose to observe pericytes at E14.5 because at this timepoint v/p are abundant in wild-type animals in several tissues, including the developing spinal cord and intercostal vasculature. Figure 4 demonstrates whole-mount visualization of the v/p cell populations in E14.5 wild-type embryos and the most severe F series mutant embryo (F7/−). After examining several litters of F series mutant embryos bearing the XlacZ4 marker, it was clear that the entire panel of F series homozygous mutant embryos could be distinguished from wild-type embryos simply by the degree that blood vessels had acquired v/p (data not shown).


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

Tallquist MD, French WJ, Soriano P - PLoS Biol. (2003)

Reduction in V/P Cells in the Thoracic Region of E14.5 EmbryosVentral view of E14.5 wild-type and F7/− littermates with the XlacZ4 mouse marker background. β-Galactosidase-positive nuclei represent v/p cells. Th, thymus.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC261889&req=5

pbio.0000052-g004: Reduction in V/P Cells in the Thoracic Region of E14.5 EmbryosVentral view of E14.5 wild-type and F7/− littermates with the XlacZ4 mouse marker background. β-Galactosidase-positive nuclei represent v/p cells. Th, thymus.
Mentions: To determine whether the reduction in v/p was caused by a gradual loss or a developmental defect, we examined pericyte populations in wild-type and mutant embryos. The XlacZ4 mouse marker can be used to identify specific v/p cell populations as early as E12.5. We chose to observe pericytes at E14.5 because at this timepoint v/p are abundant in wild-type animals in several tissues, including the developing spinal cord and intercostal vasculature. Figure 4 demonstrates whole-mount visualization of the v/p cell populations in E14.5 wild-type embryos and the most severe F series mutant embryo (F7/−). After examining several litters of F series mutant embryos bearing the XlacZ4 marker, it was clear that the entire panel of F series homozygous mutant embryos could be distinguished from wild-type embryos simply by the degree that blood vessels had acquired v/p (data not shown).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Program in Developmental Biology and Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. michelle.tallquist@utsouthwestern.edu

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus