Platelet-Derived Growth Factor C Deficiency in C57BL/6 Mice Leads to Abnormal Cerebral Vascularization, Loss of Neuroependymal Integrity, and Ventricular Abnormalities

Platelet-derived growth factors (PDGFs) and their tyrosine kinase receptors (PDGFRs) are known to play important roles during development of the lungs, central nervous system (CNS), and skeleton and in several diseases. PDGF-C is a ligand for the tyrosine kinase receptor PDGFRα. Mutations in the gene encoding PDGF-C have been linked to clefts of the lip and/or palate in humans, and ablation of PDGF-C in 129/Sv background mice results in death during the perinatal period. In this study, we report that ablation of PDGF-C in C57BL/6 mice results in a milder phenotype than in 129/Sv mice, and we present a phenotypic characterization of PDGF-C deficiency in the adult murine CNS. Multiple congenital defects were observed in the CNS of PDGF-C–null C57BL/6 mice, including cerebral vascular abnormalities with abnormal vascular smooth muscle cell coverage. In vivo imaging of mice deficient in PDGF-C also revealed cerebral ventricular abnormalities, such as asymmetry of the lateral ventricles and hypoplasia of the septum, reminiscent of cavum septum pellucidum in humans. We further noted that PDGF-C–deficient mice displayed a distorted ependymal lining of the lateral ventricles, and we found evidence of misplaced neurons in the ventricular lining. We conclude that PDGF-C plays a critical role in the development of normal cerebral ventricles and neuroependymal integrity as well as in normal cerebral vascularization. Platelet-derived growth factors (PDGFs) and their tyrosine kinase receptors (PDGFRs) are known to play important roles during development of the lungs, central nervous system (CNS), and skeleton and in several diseases. PDGF-C is a ligand for the tyrosine kinase receptor PDGFRα. Mutations in the gene encoding PDGF-C have been linked to clefts of the lip and/or palate in humans, and ablation of PDGF-C in 129/Sv background mice results in death during the perinatal period. In this study, we report that ablation of PDGF-C in C57BL/6 mice results in a milder phenotype than in 129/Sv mice, and we present a phenotypic characterization of PDGF-C deficiency in the adult murine CNS. Multiple congenital defects were observed in the CNS of PDGF-C–null C57BL/6 mice, including cerebral vascular abnormalities with abnormal vascular smooth muscle cell coverage. In vivo imaging of mice deficient in PDGF-C also revealed cerebral ventricular abnormalities, such as asymmetry of the lateral ventricles and hypoplasia of the septum, reminiscent of cavum septum pellucidum in humans. We further noted that PDGF-C–deficient mice displayed a distorted ependymal lining of the lateral ventricles, and we found evidence of misplaced neurons in the ventricular lining. We conclude that PDGF-C plays a critical role in the development of normal cerebral ventricles and neuroependymal integrity as well as in normal cerebral vascularization. Platelet-derived growth factors (PDGFs) and their tyrosine kinase receptors (PDGFRs) are well known to play crucial roles during development and in several diseases.1Andrae J. Gallini R. Betsholtz C. Role of platelet-derived growth factors in physiology and medicine.Genes Dev. 2008; 22: 1276-1312Crossref PubMed Scopus (1736) Google Scholar Currently, there are four known PDGFs, PDGF-A through PDGF-D, that signal via two PDGFRs, PDGFRα and PDGFRβ. PDGFRβ signaling has been shown to primarily direct the development of vascular mural cells, whereas PDGFRα signaling has been implicated in numerous developmental processes, including gonad, lung, central nervous system (CNS), and skeletal development. PDGF-C is secreted as a latent disulphide-linked homodimer (PDGF-CC) that requires proteolytic activation to induce signaling via PDGFRα.2Li X. Pontén A. Aase K. Karlsson L. Abramsson A. Uutela M. Bäckström G. Hellström M. Boström H. Li H. Soriano P. Betsholtz C. Heldin C.H. Alitalo K. Östman A. Eriksson U. PDGF-C is a new protease-activated ligand for the PDGF α-receptor.Nat Cell Biol. 2000; 2: 302-309Crossref PubMed Scopus (508) Google Scholar We previously showed that tissue plasminogen activator can activate PDGF-CC3Fredriksson L. Li H. Fieber C. Li X. Eriksson U. Tissue plasminogen activator is a potent activator of PDGF-CC.EMBO J. 2004; 23: 3793-3802Crossref PubMed Scopus (157) Google Scholar and that activation in the neurovascular unit leads to increased vascular permeability.4Su E.J. Fredriksson L. Geyer M. Folestad E. Cale J. Andrae J. Gao Y. Pietras K. Mann K. Yepes M. Strickland D.K. Betsholtz C. Eriksson U. Lawrence D.A. Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke.Nat Med. 2008; 14: 731-737Crossref PubMed Scopus (365) Google Scholar PDGF-C/PDGFRα signaling was found to be involved in the loss of blood-brain barrier function during stroke, and pharmacologic inhibition of PDGF signaling with the receptor antagonist imatinib or with neutralizing antibodies to PDGF-C improved blood-brain barrier integrity.4Su E.J. Fredriksson L. Geyer M. Folestad E. Cale J. Andrae J. Gao Y. Pietras K. Mann K. Yepes M. Strickland D.K. Betsholtz C. Eriksson U. Lawrence D.A. Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke.Nat Med. 2008; 14: 731-737Crossref PubMed Scopus (365) Google Scholar However, further dissection of this novel role for PDGF signaling using PDGF-C– or PDGFRα–deficient mice was not feasible since PDGFRα and PDGF-C ablation in mice was reported to result in embryonic or perinatal lethality.5Soriano P. The PDGF α receptor is required for neural crest cell development and for normal patterning of the somites.Development. 1997; 124: 2691-2700Crossref PubMed Google Scholar, 6Ding H. Wu X. Boström H. Kim I. Wong N. Tsoi B. O'Rourke M. Koh G.Y. Soriano P. Betsholtz C. Hart T.C. Marazita M.L. Field L.L. Tam P.P. Nagy A. A specific requirement for PDGF-C in palate formation and PDGFR-α signaling.Nat Genet. 2004; 36: 1111-1116Crossref PubMed Scopus (176) Google Scholar However, the severity of PDGF-C ablation seems to depend on the genetic background of the mice.7Betsholtz C. Insight into the physiological functions of PDGF through genetic studies in mice.Cytokine Growth Factor Rev. 2004; 15: 215-228Crossref PubMed Scopus (319) Google Scholar In this study, we demonstrate that PDGF-C deficiency on a C57BL/6 background is largely compatible with postnatal life, thus offering the opportunity to study the physiologic and pathophysiologic roles of this protein in the adult mouse. However, these PDGF-C–deficient mutants present numerous congenital defects, including cerebral ventricular malformations with a distorted ependymal lining and abnormal cerebral vascularization. The ventricular defects associated with PDGF-C ablation, such as asymmetry of the lateral ventricles and hypoplastic development of the septum separating the lateral ventricles, were unexpected since this has not been linked to PDGFRα signaling previously.1Andrae J. Gallini R. Betsholtz C. Role of platelet-derived growth factors in physiology and medicine.Genes Dev. 2008; 22: 1276-1312Crossref PubMed Scopus (1736) Google Scholar It is likely that these cerebral ventricular abnormalities are masked by the more severe phenotype reported for PDGF-C ablation in 129/Sv background mice and by the embryonic lethality associated with PDGFRα deficiency.5Soriano P. The PDGF α receptor is required for neural crest cell development and for normal patterning of the somites.Development. 1997; 124: 2691-2700Crossref PubMed Google Scholar, 6Ding H. Wu X. Boström H. Kim I. Wong N. Tsoi B. O'Rourke M. Koh G.Y. Soriano P. Betsholtz C. Hart T.C. Marazita M.L. Field L.L. Tam P.P. Nagy A. A specific requirement for PDGF-C in palate formation and PDGFR-α signaling.Nat Genet. 2004; 36: 1111-1116Crossref PubMed Scopus (176) Google Scholar These findings are of interest because the molecular mechanisms underlying brain ventricle formation remain poorly understood.8Lowery L.A. Sive H. Initial formation of zebrafish brain ventricles occurs independently of circulation and requires the nagie oko and snakehead/atp1a1a 1 gene products.Development. 2005; 132: 2057-2067Crossref PubMed Scopus (157) Google Scholar Taken together, the data presented herein will aid in our understanding of the role of PDGF-C during CNS development, and the description of viable PDGF-C–deficient mice presents an excellent genetic tool for the study of modifier genes of PDGF signaling in mice and for the potential to study the role of PDGF-C in adult mice. The generation of PDGF-C–deficient mice has been described previously.6Ding H. Wu X. Boström H. Kim I. Wong N. Tsoi B. O'Rourke M. Koh G.Y. Soriano P. Betsholtz C. Hart T.C. Marazita M.L. Field L.L. Tam P.P. Nagy A. A specific requirement for PDGF-C in palate formation and PDGFR-α signaling.Nat Genet. 2004; 36: 1111-1116Crossref PubMed Scopus (176) Google Scholar These mice were backcrossed onto a C57BL/6J genetic background. For localization of PDGFRα, we used reporter mice heterozygous for green fluorescent protein (GFP) expression in the nucleus of PDGFRα-positive cells (Pdgfrα:GFP).9Hamilton T.G. Klinghoffer R.A. Corrin P.D. Soriano P. Evolutionary divergence of platelet-derived growth factor α receptor signaling mechanisms.Mol Cell Biol. 2003; 23: 4013-4025Crossref PubMed Scopus (304) Google Scholar All mice used were age- and sex-matched heterozygous The were by the for the of and the Tissue for and was using All were using a a and are of the were with with in the were For the were in and were for and using For and were in for 1 and were in were by of using for and of in for system The antibodies used were antibodies PDGF-C as reported by Li X. Pontén A. Aase K. Karlsson L. Abramsson A. Uutela M. Bäckström G. Hellström M. Boström H. Li H. Soriano P. Betsholtz C. Heldin C.H. Alitalo K. Östman A. Eriksson U. PDGF-C is a new protease-activated ligand for the PDGF α-receptor.Nat Cell Biol. 2000; 2: 302-309Crossref PubMed Scopus (508) Google antibodies were and signal using the system to the The signal was using the were with or and in background was observed not For were whereas were in on were in for and were in in for to on The antibodies used were muscle protein was by in 1 and antibodies were and the were using In the of was using system was to or brain were with and in for reporter gene expression was by with and 1 of in in the All imaging was the for of of the imaging the mice were with and the was using was using a A was used to the of the mice. were using a with the of of of and of 1 The development was used to in ventricular and the was All were using not All are as the of in the The are on of two to of For of the a was for a was with as and our findings that PDGF-C/PDGFRα signaling was involved in the of blood-brain barrier we were in a understanding of the role of this signaling in the adult murine CNS. For our we the expression of PDGF-C in adult brain by These studies revealed expression of PDGF-C protein in adult murine in such as the nucleus separating the lateral ventricles, cerebral and expression was largely in and C57BL/6 mice by expression of the reporter to the H. Wu X. Boström H. Kim I. Wong N. Tsoi B. O'Rourke M. Koh G.Y. Soriano P. Betsholtz C. Hart T.C. Marazita M.L. Field L.L. Tam P.P. Nagy A. A specific requirement for PDGF-C in palate formation and PDGFR-α signaling.Nat Genet. 2004; 36: 1111-1116Crossref PubMed Scopus (176) Google Scholar It has previously been reported that PDGF-C–deficient mice on a 129/Sv background to and by a of the H. Wu X. Boström H. Kim I. Wong N. Tsoi B. O'Rourke M. Koh G.Y. Soriano P. Betsholtz C. Hart T.C. Marazita M.L. Field L.L. Tam P.P. Nagy A. A specific requirement for PDGF-C in palate formation and PDGFR-α signaling.Nat Genet. 2004; 36: 1111-1116Crossref PubMed Scopus (176) Google Scholar backcrossed onto a C57BL/6 ablation to as in a severe thus the of studies in adult PDGF-C–deficient mice. We found that a of the mice the perinatal However, we noted a were viable were also in the mice and two mice, and normal for than phenotype was to mice also presented with an of or a in the not a skeletal previously observed in H. Wu X. Boström H. Kim I. Wong N. Tsoi B. O'Rourke M. Koh G.Y. Soriano P. Betsholtz C. Hart T.C. Marazita M.L. Field L.L. Tam P.P. Nagy A. A specific requirement for PDGF-C in palate formation and PDGFR-α signaling.Nat Genet. 2004; 36: 1111-1116Crossref PubMed Scopus (176) Google Scholar In mice were and and not mice were reported to formation and of are of vascular defects and abnormal vascular H. Wu X. Boström H. Kim I. Wong N. Tsoi B. O'Rourke M. Koh G.Y. Soriano P. Betsholtz C. Hart T.C. Marazita M.L. Field L.L. Tam P.P. Nagy A. A specific requirement for PDGF-C in palate formation and PDGFR-α signaling.Nat Genet. 2004; 36: 1111-1116Crossref PubMed Scopus (176) Google Scholar using a for vascular cells, and muscle a for vascular smooth muscle cells also revealed abnormal in the of adult mice with In the vascular with the whereas in the vascular was more with an in to mice. was by of the a in and in mice with and with antibodies cell not is with studies of murine that of PDGF-C a in H. Fredriksson L. Li X. Eriksson U. is a potent and growth 2003; 22: PubMed Scopus Google Scholar, E. N. J. L.L. PDGF-C of in a of and the to PubMed Scopus Google Scholar whereas of PDGF-C expression a to with E. N. J. L.L. PDGF-C of in a of and the to PubMed Scopus Google Scholar of the muscle in mice more with was unexpected as increased is of a more vascular However, the not to normal the in of a and the as in mice, the in mice were the cell and In the in the adult murine brain of mice to have normal of as by with PDGFRβ and antibodies not the characterization of mice, we noted that these mice presented with lateral of by revealed that the lateral ventricles to with of the septum the of the ventricle The septum, to the septum pellucidum in humans, is the that the lateral ventricles, and in mice the ventricle that the asymmetry was not an of tissue in vivo in mice was used of the of ventricular asymmetry was the and the For the the of the lateral ventricle was using for and is as the of the to the ventricular that the of the lateral ventricles in mice was the of the In the ventricles were a of the the of the to the ventricle the revealed asymmetry of the lateral ventricles in mice with in thus the results of In mice, asymmetry was with that in mice and mice, a gene of PDGF-C in the of ventricular of adult mice with a hypoplastic septum were also observed by and two a of an adult this was noted in and mice with a hypoplastic septum were this of ventricular on the present findings of lateral ventricle abnormalities in mice and a study expression of PDGF-C in cells the ventricles in the murine K. Abramsson A. Karlsson L. Betsholtz C. Eriksson U. of PDGF-C in adult and Dev. PubMed Scopus Google Scholar we the integrity of the ependymal cell lining the lateral ventricles in adult PDGF-C mice. In mice, we noted that the ependymal herein by the ependymal development, and a PubMed Scopus Google Scholar was poorly It and and to the underlying cell not of ependymal were in These further revealed that the normal of ependymal cells was in with antibodies revealed that the in was abnormal and present in with antibodies a for C. M. C. P. L. K. L. B. M. R. cell and expression is a in the ventricular 2005; PubMed Scopus Google Scholar showed a in expression in with Taken together, these results demonstrate that ablation of PDGF-C signaling ependymal and In to ependymal abnormalities, of cells with antibodies revealed that the lining of the lateral ventricles was in mice was observed in of the with These also to as cells, are to be the neural cells of the adult I. D.A. A. are neural cells in the adult PubMed Scopus Google Scholar that these cells have been reported to PDGFRα in the adult M. A. A. cells are neural cells in the adult that in to increased PDGF PubMed Scopus Google Scholar A study has linked PDGF-C signaling to in P. C. Li Y. A. X. B. P. L. Y. H. J. N. Y. Li X. of PDGF-CC neurons in brain and by Med. PubMed Scopus Google Scholar to study the of PDGF-C ablation on the in mice. for a for that the of cells in mice was to that in mice These revealed the lateral ventricles in mice neurons the ependymal cell lining A and was not in The in are in misplaced neurons are of a since is that these neurons have to to their in the cerebral PDGF-C deficiency results in defects in we the in adult mice using for to and showed an in mice, not increased in mice of PDGFRα in the the receptor for X. Pontén A. Aase K. Karlsson L. Abramsson A. Uutela M. Bäckström G. Hellström M. Boström H. Li H. Soriano P. Betsholtz C. Heldin C.H. Alitalo K. Östman A. Eriksson U. PDGF-C is a new protease-activated ligand for the PDGF α-receptor.Nat Cell Biol. 2000; 2: 302-309Crossref PubMed Scopus (508) Google Scholar has been and is well that PDGFRα signaling is for cell E.J. PDGF receptors in the during PDGF expression to be to cells of the Google Scholar, M. Karlsson L. Abramsson A. H. K. C.H. Betsholtz C. development and severe in PDGF-A PubMed Google Scholar However, studies have that PDGFRα is also by neurons in the adult and has been that PDGF-C/PDGFRα signaling be critical for in P. C. Li Y. A. X. B. P. L. Y. H. J. N. Y. Li X. of PDGF-CC neurons in brain and by Med. PubMed Scopus Google Scholar, L. B. receptor is by of the central nervous PubMed Scopus Google Scholar to these the expression and role of PDGFRα in the we PDGFRα is in the adult murine brain to potential cells of PDGF-C For this we used reporter T.G. Klinghoffer R.A. Corrin P.D. Soriano P. Evolutionary divergence of platelet-derived growth factor α receptor signaling mechanisms.Mol Cell Biol. 2003; 23: 4013-4025Crossref PubMed Scopus (304) Google Scholar of brain adult mice with the in the nucleus of revealed evidence of expression of PDGFRα in neurons in vivo In we not with expression of PDGFRα reporter and the and green in to the of neurons and These expression of PDGFRα in neurons in the adult are with the normal of in the of mice of brain adult PDGFRα reporter mice with revealed that the PDGFRα reporter gene was in cells such as and these data that in vivo PDGF-C is not required for through PDGFRα signaling on the present data are with studies that PDGFRα be important for cell development and by Andrae J. Gallini R. Betsholtz C. Role of platelet-derived growth factors in physiology and medicine.Genes Dev. 2008; 22: 1276-1312Crossref PubMed Scopus (1736) Google of the known ligand for PDGFRα, has been reported to the of and in the perinatal murine M. Karlsson L. Abramsson A. H. K. C.H. Betsholtz C. development and severe in PDGF-A PubMed Google Scholar However, PDGF-A ablation has on the of in the cerebral PDGF-C is in the adult cerebral A and and PDGFRα is in and and we ablation of PDGF-C the of in this of the We found that the of in the of adult mice was to that of It that PDGF-C functions in with PDGF-A during embryonic and perinatal in the cerebral that this is not in the adult mice study that loss of PDGF-C in C57BL/6 mice is compatible with postnatal offering the opportunity to study the physiologic and pathophysiologic roles of this protein in the adult mouse. However, postnatal these data demonstrate the of congenital defects in the CNS of mice, such as cerebral vascular abnormalities, and lateral ventricles with distorted ependymal lining. The milder phenotype of PDGF-C ablation in C57BL/6 mice will the study of developmental roles of by the more severe phenotype in H. Wu X. Boström H. Kim I. Wong N. Tsoi B. O'Rourke M. Koh G.Y. Soriano P. Betsholtz C. Hart T.C. Marazita M.L. Field L.L. Tam P.P. Nagy A. A specific requirement for PDGF-C in palate formation and PDGFR-α signaling.Nat Genet. 2004; 36: 1111-1116Crossref PubMed Scopus (176) Google Scholar The that phenotype severity on genetic background also an opportunity to study modifier genes of PDGF signaling in mice. The unexpected that PDGF-C ablation in C57BL/6 mice is associated with cerebral ventricular defects was because this has not been linked to PDGFRα signaling J. Gallini R. Betsholtz C. Role of platelet-derived growth factors in physiology and medicine.Genes Dev. 2008; 22: 1276-1312Crossref PubMed Scopus (1736) Google Scholar and because the molecular mechanisms underlying brain ventricle formation remain poorly understood.8Lowery L.A. Sive H. Initial formation of zebrafish brain ventricles occurs independently of circulation and requires the nagie oko and snakehead/atp1a1a 1 gene products.Development. 2005; 132: 2057-2067Crossref PubMed Scopus (157) Google Scholar The ventricle in mice to of the septum, the that the lateral In mice, we noted development of the septum, is reminiscent of cavum septum pellucidum in humans. A cavum of the septum is present is by to as the in a A. L. Y. P. for in and PubMed Scopus Google Scholar of a cavum septum pellucidum in is a for neural the is largely cavum septum a of brain PubMed Scopus Google Scholar However, has been that is likely to of such as the and J. J. The of cavum is increased in PubMed Scopus Google Scholar, P. A. cavum in with and 2000; PubMed Scopus Google Scholar we report expression of A cavum septum pellucidum in the adult has also been associated with such as clefts of the lip and/or P. L. J. of a brain in with clefts of the lip and/or PubMed Scopus Google Scholar previously PDGF-C ablation in 129/Sv mice results in a of the H. Wu X. Boström H. Kim I. Wong N. Tsoi B. O'Rourke M. Koh G.Y. Soriano P. Betsholtz C. Hart T.C. Marazita M.L. Field L.L. Tam P.P. Nagy A. A specific requirement for PDGF-C in palate formation and PDGFR-α signaling.Nat Genet. 2004; 36: 1111-1116Crossref PubMed Scopus (176) Google Scholar and in the gene have been shown to with clefts of the lip and/or A. M. K. C. of of genes using two studies PubMed Scopus Google Scholar, Marazita M.L. Hart P.P. Field L.L. T.G. M. A. R. Hart T.C. The PDGF-C and is associated with Genet. PubMed Scopus Google Scholar The cerebral ventricles in adult are with an of cells, the ependymal cells, that are important for normal brain The a barrier brain and 14: PubMed Scopus Google Scholar The present study that PDGF-C ablation defects in the ependymal lining of the lateral ventricles and in the underlying These defects are by the loss of the normal ependymal cell and by ependymal and loss of cells in the that PDGF-C/PDGFRα signaling the formation of normal lateral ventricle lining. These are of interest since the is to be the of and cells in the adult brain and the molecular ependymal is not I. D.A. A. are neural cells in the adult PubMed Scopus Google Scholar the present not loss of PDGF-C the important ependymal or by the cell in the is to that loss of PDGF-C during development the of are to ependymal as well as cells in the M. A. A. cells are neural cells in the adult that in to increased PDGF PubMed Scopus Google Scholar, N. N. A. ependymal cells are and are cells during 2005; PubMed Scopus Google Scholar, A. to adult neural cells in the A. 2004; PubMed Scopus Google Scholar that this of is the is known to expression of PDGFRα as as embryonic J. I. M. Platelet-derived growth factor in ventricular cells and in Cell PubMed Scopus Google Scholar and that the evidence of ependymal is in the of the neural a in expression of PDGF-C has been K. Abramsson A. Karlsson L. Betsholtz C. Eriksson U. of PDGF-C in adult and Dev. PubMed Scopus Google Scholar It will be to the PDGF-C mutants herein to further the molecular of PDGF signaling development. malformations and loss of neuroependymal integrity have been linked to and neural defects and to and PubMed Scopus Google Scholar, J. G. E. J. R. J. R. R. of neural the ventricular and in Genet. PubMed Scopus Google Scholar In the lateral ventricular of mice, we found misplaced neurons the ependymal a in as the J. 2005; PubMed Scopus Google Scholar and in of death L. in death and death of to Dev. PubMed Scopus Google Scholar In we also found of with as an abnormal of and of the lateral these defects are to ependymal abnormalities associated with PDGF-C ablation to be on our we that PDGF-C and receptor PDGFRα are in the of ischemic in E.J. Fredriksson L. Geyer M. Folestad E. Cale J. Andrae J. Gao Y. Pietras K. Mann K. Yepes M. Strickland D.K. Betsholtz C. Eriksson U. Lawrence D.A. Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke.Nat Med. 2008; 14: 731-737Crossref PubMed Scopus (365) Google Scholar and a has been to the and of the PDGF-C/PDGFRα signaling in with of the The is that this signaling will the of by the integrity of the blood-brain However, for this to is important to that PDGF-C is also in the neurovascular unit in In studies in with reported we that the expression of PDGF-C in the brain seems to be with expression in such as in the and not of to that in mice, including localization the a role for PDGF-C in the neurovascular unit in humans. A study has that PDGF-C is a potent factor and inhibition of the PDGF-C/PDGFRα signaling in P. C. Li Y. A. X. B. P. L. Y. H. J. N. Y. Li X. of PDGF-CC neurons in brain and by Med. PubMed Scopus Google Scholar However, the present data not a role for PDGF-C as a factor in vivo because in this study, mice displayed normal of neurons in the brain ablation of PDGF-C because we found evidence of PDGFRα expression on neurons in The present results are also with of studies that have shown that PDGFRα is critical for not for J. Gallini R. Betsholtz C. Role of platelet-derived growth factors in physiology and medicine.Genes Dev. 2008; 22: 1276-1312Crossref PubMed Scopus (1736) Google Scholar, M. A. A. cells are neural cells in the adult that in to increased PDGF PubMed Scopus Google Scholar In to a the present data demonstrate the of congenital defects in the CNS of mice, including cerebral vascular and ventricular These developmental defects were not noted in the study by and P. C. Li Y. A. X. B. P. L. Y. H. J. N. Y. Li X. of PDGF-CC neurons in brain and by Med. PubMed Scopus Google Scholar and the of their data with mice. We that these congenital abnormalities to be using mice as a genetic tool in the of pathophysiologic roles of PDGF-C and PDGFRα in the adult CNS. an study has our that PDGFRα signaling in vivo the integrity of the blood-brain B. N. H. J. J. PDGFR-α inhibition blood-brain barrier PubMed Scopus Google Scholar In these data demonstrate that PDGF-C plays an important role in the formation of normal cerebral and normal cerebral ventricles and in neuroependymal The mice herein present an excellent genetic tool for further and underlying molecular mechanisms of cerebral ventricle and ependymal development and will be to these mice to study the PDGF and such as cavum septum pellucidum and and to further into the cell in the We Soriano for the reporter mice and M. for

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.