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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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Pericytes within the E14.5 Nervous System of F Series Mutant Embryos(A) Representative sections through neural tubes of embryos from the homozygous F allelic series. (B) Representative sections of embryos from the hemizygous allelic series (F series mutant with one copy of the  allele). Sections are from the rostral level between the heart and kidney. Pericytes are visualized by nuclear-localized β-galactosidase staining in cells committed to the v/p lineage. Sections are 7 μm.
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pbio.0000052-g005: Pericytes within the E14.5 Nervous System of F Series Mutant Embryos(A) Representative sections through neural tubes of embryos from the homozygous F allelic series. (B) Representative sections of embryos from the hemizygous allelic series (F series mutant with one copy of the allele). Sections are from the rostral level between the heart and kidney. Pericytes are visualized by nuclear-localized β-galactosidase staining in cells committed to the v/p lineage. Sections are 7 μm.

Mentions: To obtain a quantitative view of these results, we chose to focus on the spinal cord pericyte population. These cells begin to form at E10.5 in a rostral-to-caudal fashion in the embryo and require PDGFRβ signals for development (Levéen et al. 1994). Cross-sections through the developing spinal cord (neural tube) provide a relatively uniform area for quantitation. We can consistently identify a particular maturation stage of the developing vasculature based on its axial level within the embryo, and the pericytes can often be found as isolated cells (Figure 5). Using the entire panel of PDGFRβ mutant mice, we compared pericyte numbers between the different F series mutants (Figures 5 and 6). In all mutants examined, with the exception of the F1 mutation, we observed a decreased incidence of pericytes when compared to the wild-type embryos. The reduction in pericyte numbers ranged from 42% to 77%. This reduction was present at the more mature axial level of the heart as well as at the axial level of the kidney.


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

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

Pericytes within the E14.5 Nervous System of F Series Mutant Embryos(A) Representative sections through neural tubes of embryos from the homozygous F allelic series. (B) Representative sections of embryos from the hemizygous allelic series (F series mutant with one copy of the  allele). Sections are from the rostral level between the heart and kidney. Pericytes are visualized by nuclear-localized β-galactosidase staining in cells committed to the v/p lineage. Sections are 7 μm.
© Copyright Policy
Related In: Results  -  Collection

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

pbio.0000052-g005: Pericytes within the E14.5 Nervous System of F Series Mutant Embryos(A) Representative sections through neural tubes of embryos from the homozygous F allelic series. (B) Representative sections of embryos from the hemizygous allelic series (F series mutant with one copy of the allele). Sections are from the rostral level between the heart and kidney. Pericytes are visualized by nuclear-localized β-galactosidase staining in cells committed to the v/p lineage. Sections are 7 μm.
Mentions: To obtain a quantitative view of these results, we chose to focus on the spinal cord pericyte population. These cells begin to form at E10.5 in a rostral-to-caudal fashion in the embryo and require PDGFRβ signals for development (Levéen et al. 1994). Cross-sections through the developing spinal cord (neural tube) provide a relatively uniform area for quantitation. We can consistently identify a particular maturation stage of the developing vasculature based on its axial level within the embryo, and the pericytes can often be found as isolated cells (Figure 5). Using the entire panel of PDGFRβ mutant mice, we compared pericyte numbers between the different F series mutants (Figures 5 and 6). In all mutants examined, with the exception of the F1 mutation, we observed a decreased incidence of pericytes when compared to the wild-type embryos. The reduction in pericyte numbers ranged from 42% to 77%. This reduction was present at the more mature axial level of the heart as well as at the axial level of the kidney.

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