Limits...
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.

Show MeSH
Vascular Smooth Muscle Cells of the Coronary Arteries(Top) Whole-mount views of P21 hearts from littermates of the F5 alleles of mutant mice. Hearts were sliced coronally, and the ventral surface was photographed. The F5/− heart was sliced disproportionately and therefore appears to be smaller.(Bottom) P28 hearts from wild-type and F1 littermates. Hearts were sliced sagittally. Both the left and right views are shown.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC261889&req=5

pbio.0000052-g009: Vascular Smooth Muscle Cells of the Coronary Arteries(Top) Whole-mount views of P21 hearts from littermates of the F5 alleles of mutant mice. Hearts were sliced coronally, and the ventral surface was photographed. The F5/− heart was sliced disproportionately and therefore appears to be smaller.(Bottom) P28 hearts from wild-type and F1 littermates. Hearts were sliced sagittally. Both the left and right views are shown.

Mentions: We examined the blood vessels of F series homozygous mice by histology and detected no gross abnormalities (data not shown). To obtain a more global perspective of v/p cell populations, we introduced the XlacZ4 transgenic marker into our F series mutant mice. The XlacZ4 transgenic mouse expresses nuclear β-galactosidase in certain populations of differentiated, nonproliferating v/p cells in the embryo and the adult (Tidhar et al. 2001). As described below, using this marker in adult animals, we identified vascular defects in the F5 and F7 mice in the tissues of the eyes, hearts, and brains (see Figures 7, 8, and 9; data not shown). This observation suggests that both the F5 and F7 alleles function suboptimally in tissues known to require PDGFRβ signal transduction (Lindahl et al. 1997a; Hellström et al. 1999; Enge et al. 2002). Although both of these mutations cause notable phenotypes in some v/p populations, we have not observed pathologies in all populations of PDGFRβ-dependent v/p cells. V/p cell populations with no overt phenotype in the F5 and F7 mice include the kidney mesangial cells and pericytes in the skin and skeletal muscle (data not shown). We have observed a modest decrease in the number of nuclei present in F5/F5 and F5/− kidney glomeruli, but have not detected glomerulosclerosis with Masson trichrome stain (data not shown). The lack of any pathological phenotype in these tissues suggests either that the reduction in v/p cells is less severe than in the case of the PDGFRβ mice, that the PDGFRα may be coexpressed in these same tissues, or that these tissues can function adequately even with reduced v/p cell numbers.


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

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

Vascular Smooth Muscle Cells of the Coronary Arteries(Top) Whole-mount views of P21 hearts from littermates of the F5 alleles of mutant mice. Hearts were sliced coronally, and the ventral surface was photographed. The F5/− heart was sliced disproportionately and therefore appears to be smaller.(Bottom) P28 hearts from wild-type and F1 littermates. Hearts were sliced sagittally. Both the left and right views are shown.
© Copyright Policy
Related In: Results  -  Collection

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

pbio.0000052-g009: Vascular Smooth Muscle Cells of the Coronary Arteries(Top) Whole-mount views of P21 hearts from littermates of the F5 alleles of mutant mice. Hearts were sliced coronally, and the ventral surface was photographed. The F5/− heart was sliced disproportionately and therefore appears to be smaller.(Bottom) P28 hearts from wild-type and F1 littermates. Hearts were sliced sagittally. Both the left and right views are shown.
Mentions: We examined the blood vessels of F series homozygous mice by histology and detected no gross abnormalities (data not shown). To obtain a more global perspective of v/p cell populations, we introduced the XlacZ4 transgenic marker into our F series mutant mice. The XlacZ4 transgenic mouse expresses nuclear β-galactosidase in certain populations of differentiated, nonproliferating v/p cells in the embryo and the adult (Tidhar et al. 2001). As described below, using this marker in adult animals, we identified vascular defects in the F5 and F7 mice in the tissues of the eyes, hearts, and brains (see Figures 7, 8, and 9; data not shown). This observation suggests that both the F5 and F7 alleles function suboptimally in tissues known to require PDGFRβ signal transduction (Lindahl et al. 1997a; Hellström et al. 1999; Enge et al. 2002). Although both of these mutations cause notable phenotypes in some v/p populations, we have not observed pathologies in all populations of PDGFRβ-dependent v/p cells. V/p cell populations with no overt phenotype in the F5 and F7 mice include the kidney mesangial cells and pericytes in the skin and skeletal muscle (data not shown). We have observed a modest decrease in the number of nuclei present in F5/F5 and F5/− kidney glomeruli, but have not detected glomerulosclerosis with Masson trichrome stain (data not shown). The lack of any pathological phenotype in these tissues suggests either that the reduction in v/p cells is less severe than in the case of the PDGFRβ mice, that the PDGFRα may be coexpressed in these same tissues, or that these tissues can function adequately even with reduced v/p cell numbers.

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