Physiology 20: 390-397, 2005;
doi:10.1152/physiol.00035.2005
1548-9213/05 $8.00
Physiology, Vol. 20, No. 6, 390-397,
December 2005
© 2005 Int. Union Physiol. Sci./Am. Physiol. Soc.
REVIEW
Ras-Related Signaling Pathways in Valve Development: Ebb and Flow
Katherine E. Yutzey,
Melissa Colbert and
Jeffrey Robbins
Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio
Jeff.Robbins{at}cchmc.org
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Abstract
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Congenital heart defects affect ~1 in every 100 live births, and deficits in the formation of the mitral, tricuspid, and outflow tract valves account for 20–25% of all cardiac malformations. Mutations in genes that affect Ras signaling have been identified in individuals with congenital valve disease associated with Noonan syndrome and neurofibromatosis type 1. Dissection of Ras-related signaling pathways during valvulogenesis provides seminal insight into cellular and molecular mechanisms that contribute to congenital heart disease.
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Valve Development and Congenital Heart Disease
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The heart is the first organ to form in the embryo, and congenital cardiovascular anomalies are responsible for between 16–45% of prenatal deaths (38, 54, 55). With the increased use of echocardiography in newborns and the advent of fetal ultrasound, the incidence of congenital heart defects (CHD) is now estimated as between 1.2–1.4% of all live births (Table 1
) (25). Newborn death due to CHD is second only to infection, and 38% of children diagnosed with a defect will undergo surgical or catheterization-based interventions at least once in their lifetime.
Valvular defects account for 20–25% of CHD (25, 37) and include bicuspid aortic valve, pulmonary, or tricuspid atresia and Ebstein’s anomaly. Congenital heart valve disease can be caused by genetic or environmental factors, and, with rare exceptions, the specific etiologies of the lesions are unknown. However, recent genetic and biochemical data have identified mutations responsible for congenital heart valve disease associated with Noonan syndrome (NS) and neurofibromatosis type 1 (NF1). Strikingly, the mutations in each of these genes affect Ras-related signal transduction.
Heart valve formation during vertebrate embryogenesis is characterized by the initial formation of endocardial cushions in the atrioventricular (AV) canal and outflow tract (OFT), followed by the proliferation of heart valve progenitor cells and the remodeling of primordial valves (3, 44, 48). At the end of this process, the mature valves consist of elongated leaflets composed primarily of stratified extracellular matrix (ECM) layers and supporting structures. The early stages of endocardial cushion formation and remodeling are similar, but not identical, for the arterial semilunar valves and for the tricuspid and mitral AV valves. In both the AV canal and OFT, endocardial cushions form through an epithelial-to-mesenchymal transition (EMT) in which a subpopulation of endothelial cells transdifferentiates into mesenchyme in response to signals secreted from the myocardium (44). These cushions then go through a highly proliferative phase and fuse to form highly cellular undifferentiated valve primordia that contain the precursors of the individual valves (13, 36). The valve primordia undergo a process of remodeling characterized by reduced proliferation and generation of organized collagen-, elastin-, and proteoglycan-rich ECM strata of the elongated leaflets. Although the mature structures of the semilunar valve cusps are different from the AV valve leaflets and supporting chordae tendineae, the stratification of the valve ECM compartments is similar for both sets of valves relative to the direction of blood flow in the mature heart. However, the semilunar and AV valves differ in the cells that migrate into these structures from extracardiac sources in the embryo, with neural crest cells contributing to the OFT and epicardial-derived cells incorporating into the AV canal.
Formation of the semilunar and AV valves is dependent on common signaling pathways, although the specific components of each pathway may be different for the individual valves. Studies in mouse, chicken, and zebrafish embryos as well as human genetic analyses have implicated several signaling mechanisms including TGF-ß, bone morphogenetic protein (BMP), Wnt, and Notch pathways in endocardial cushion formation and valve maturation. The reader is referred to a number of excellent reviews that outline in more detail the many pathways that underlie cardiac morphogenesis in general (7) and valve development in particular (3, 22, 44, 48).
Recently the importance of Ras-related signaling in heart valve formation has been underscored by identification of the molecular bases of NS and NF1 (4, 53). Therefore, this review will focus on Ras-related signaling mechanisms as a comprehensive example of a pathway that has been examined mechanistically in several animal systems and whose role in human congenital heart disease is well established.
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Ras-Related Signaling Pathways Are Affected in Human Genetic Disorders with Associated Congenital Valve Malformations
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GTP-binding proteins such as Ras act as molecular switches in a large number of signal pathways. In addition to the trimeric G proteins, which are coupled directly to their receptors (e.g., the ß-adrenergic receptor), the monomer Ras or Ras-like proteins play critical roles in many signal-transduction pathways. When Ras activation is triggered by the ligand binding to its cognate receptor, such as can occur in a receptor tyrosine kinase (RTK)-mediated event, Ras-GTP formation is promoted (FIGURE 1). Activation of Ras can have pleiotropic effects on cell metabolism, growth, proliferation, and migration. A central cascade activated by the Ras-GTPase switch is the MAPK cascade, which can lead to phosphorylation of many proteins, including transcription factors both in and out of the nucleus. We describe below how mutations that impinge upon this pathway’s activity have led to fundamental mechanistic insights into the underlying mechanisms of congenital valvular disease.
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FIGURE 1. Receptor tyrosine kinase activation and downstream signaling during valve development
After ligand binding, the receptor tyrosine kinase (RTK) homodimerizes and autophosphorylates, creating an SH2 binding domain at which a multiprotein "signalsome" assembles. Shp-2, GAB1, and Grb2 each have SH2 sites, and so, theoretically, each could make the initial contact. Activated Shp-2 results in activation of Ras through an as yet undefined process, and activated Ras, in turn, recruits Raf, a serine-threonine kinase, to the membrane. Hydrolysis of Ras-GTP to Ras-GDP results in dissociation of the Raf-Ras-GTP complex and activation of Raf, which then phosphorylates and activates MAPKK, a dual-specificity threonine-serine kinase, propagating the cascade. Shp-2 gain-of-function or neurofibromatosis type 1 loss-of-function have similar effects, prolonging active Ras signaling through the ERK branch of the MAPK pathway. ERK1/2 is able to phosphorylate a number of transcription factors both in and out of the nucleus; phosphorylation of a transcription factor in the cytoplasmic compartment can lead to nuclear entry. Although the downstream targets of ERK1/2-mediated phosphorylation are not fully defined, it is clear that its action, through transcriptional modulation, has pleiotropic effects on proliferation, cell migration, and apoptosis, affecting the processes that underlie valve development.
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NS was first described over 30 years ago (42) and, after Down syndrome, is the most common genetic condition that is associated with CHD. NS is inherited as an autosomal dominant trait in the majority of affected families, although many cases appear to be sporadic. The gross morphological presentation often includes typical facies, short stature, developmental delay, and cognitive deficits (40). CHD presents in ~80–90% of these patients, and the heart defects cover a spectrum of morphological and functional deficits, with the most common being dysplastic pulmonary valve, AV septal defects, or hypertrophic cardiomyopathy. Tetralogy of Fallot; atrial-septal defect; patent ductus arteriosus; left-sided anatomic obstruction at the subaortic, supravalvular, or valvular levels; and classic aortic coarctation have also been described (39).
A major step in understanding the molecular etiology of cardiac malformations associated with NS was achieved with the identification of mutations in PTPN11 as causative for as many as 50% of NS cases (51, 53) (Table 2). PTPN11 encodes a ubiquitously expressed protein tyrosine phosphatase (PTP), Shp-2 (src homology region 2, phosphatase 2), which contains two Src homology domains (SH2) at the amino terminus and a PTP domain at the carboxy end. Shp-2 is a member of a small protein family (the other vertebrate member being Shp-1 and, in Drosophila, corkscrew), whose members are implicated in a wide variety of signaling pathways that originate with activation of a RTK. Many of these mutations are hypothesized to result in a gain-of-function (GOF) for Shp-2 (18), that is, increased activity or prolongation of normal activity, but the functional consequences in terms of the ultimate transcriptional targets are not clear-cut. Interestingly, acquired somatic mutations in PTPN11 also have been reported in myeloid leukemia and B cell acute lymphoblastic leukemia, underlying the role this molecule can play in cell proliferation (52).
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Table 2. Mutations in genes encoding Ras-related signaling proteins that affect heart valve development in humans and mice
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NF1 is a relatively common disorder (1/4,000 births) that results in abnormal cell growth leading to the appearance of benign and malignant tumors (4). Patients with NF1 are predisposed to heart disease, and the most common cardiac defect in this population, as in the Noonan population, is pulmonary valvular stenosis (35). Loss-of-function (LOF) mutations in the neurofibromin tumor-suppressor encoding gene (NF1) have been identified in individuals with NF1 (4). NF1 mutations can also result in café au lait spots, skeletal dysplasia, optic gliomas, and Lisch nodules. The NF1 protein, which contains 2,818 amino acids, includes a GTPase-activating (GAP) domain that promotes the intrinsic GTPase activity of Ras-GTP, resulting in downregulated Ras signaling (11). NF1 LOF thus mimics Shp-2 GOF, as both result in increased or prolonged signaling through Ras.
The convergence of both NF1 and Shp-2 on RTK-mediated intracellular Ras signaling is underscored by the clinically recognized association of NS and NF1 (1), called neurofibromatosis-Noonan syndrome (NFNS). A number of possibilities arise for the concurrence of a subset of symptoms for both diseases in a single individual. First, it is possible that unique mutations in either NF1 or PTPN11 cause NFNS. Second, an additional, as yet unidentified genetic locus could be responsible. Another possibility is that mutations in NF1 and PTPN11 could simultaneously occur. Genetic analysis of the NFNS patients showed that at least two of these possibilities occur. In a comprehensive study of six NFNS patients, NF1 analysis showed that two previously undefined mutations lay within the GAP-encoding region. No mutations were detected in PTPN11, confirming that in some cases NFNS is a variant of NF1 (5). In contrast with these results, examination of another patient showed paternal inheritance of a PTPN11 mutation and a de novo mutation in NF1. Thus multiple mechanisms may cause the NFNS syndrome, although the consequences are, in both cases, altered Ras signaling.
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Ras/Raf/MEK/MAPK Signaling is Modulated by Shp-2 and NF1
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Both genetic and biochemical evidence indicate that Shp-2 enhances signaling through the EGF receptors via Ras (45). In cultured cells, Shp-2 activity is required for EGF receptor family-mediated activation of MAPK, and NS mutations in Shp-2 prolonged EGF-mediated MAPK activation (14, 18). In mice, genetic interactions between egfr and ptpn11 were established, with increased lethality and severity of valve malformations observed in animals homozygous for a hypomorphic egfr waved-2 allele that were also ptpn11+/– heterozygotes (10). The EGF receptors (EGFR/ErbB1/HER1, ErbB2, ErbB2, and ErbB4) are transmembrane RTKs that are activated when an EGF-family ligand binds and prompts the formation of a homo- or heterodimer (47) (FIGURE 1
). This results in rapid autophosphorylation of specific tyrosine residues that lie on the cytoplasmic side of the receptor. These phosphotyrosyl residues constitute specific recognition sequences for docking and/or adaptor molecules, which transduce and amplify the signal to downstream effectors, in some cases through the canonical GTPase switch, Ras (FIGURE 1).
PTPs such as Shp-2 can attenuate positive signaling through the RTKs. Alternatively, since tyrosine phosphorylation can also trigger a negative regulatory switch (e.g., the carboxy terminus of the Src family), PTPs may actually serve as positive effectors by mitigating the inhibitory effects of RTK activation. Although it is clear that Shp-2 is recruited to the RTK after receptor dimerization/SH2 phosphorylation/activation, this may be because of either direct binding through its own SH2 domains or binding indirectly through a docking protein (26). Shp-2 itself may act in some circumstances as an adaptor protein, recruiting other protein factors to a multiprotein "signalsome." Activated Shp-2 will, in turn, activate Ras, and this central GTPase "switch" (FIGURE 1) acting upstream of the Raf, MEK, and MAPK pathway can result, depending upon its context, in the positive or negative regulation of the ERK, JNK kinase, JAK/STAT, and NF-
B cascades (14, 18). During valve formation, Shp-2 activation results in prolonged and enhanced upregulation of Ras, with concomitant activation of MAPK signaling through ERK1/2 (2).
Solving the crystal structure of Shp-2 led to fundamental insights into its function (24). Although a number of data pointed to the fact that binding of Shp-2 through its SH2 domains enhanced phosphatase activity, the crystal structure clarified the structure-function relationships. Shp-2 contains a broad interaction domain or face between the SH2 amino terminal and phosphatase domains, and under basal conditions the SH2 amino terminal binds the phosphatase domain and the protein is autoinhibited. Intermolecular interactions of the SH2 amino terminal with the phosphotyrosyl residues on the RTK destabilize this stable interface, activating the phosphatase activity. Engineered modifications at the interface resulted in increased catalytic activity and biologically activated, that is, increased, Ras signaling mutants of Shp-2 (43). Together, the evidence from Drosophila, Caenorhabditis, Xenopus, and the mouse are all consistent with Shp-2 activation resulting in enhanced Ras signaling (17).
Strikingly, many of the NS mutations are clustered in the interacting portions of the SH2 amino terminal and phosphatase domains (51, 53), and modeling of the resulting structural changes reveals that the mutations’ main effect is to stabilize the active conformation. For a limited number of the mutations, increased phosphatase activity was confirmed (51), although it is by no means clear that this holds true for every NS mutation. However, when three defined NS mutations were modeled in COS-7 cells, each resulted in increased tyrosine phosphatase activity under basal conditions, and this was further augmented by EGF stimulation (18). Furthermore, the increased stability of the active formation led to a prolonged interaction with a Shp-2 signaling partner, Grb2-associated binder-1 (GAB1), which is known to be a major partner in EGF signaling (57). Upon RTK activation, GAB1 is recruited to the cell membrane, becomes tyrosyl phosphorylated, and acts as a docking protein through its multiple SH3 and SH2 domains. Although it is not clear that GAB1 is a direct substrate for Shp-2, these data are consistent with the general consensus that Shp-2 activation is necessary for full activation of the EGF signaling pathway. In its absence or at basal, ligand-unstimulated levels, there is some signaling downstream through the Ras-Raf, MEK-MAPK pathway, but Shp-2 activity is required for its prolongation.
NF1, like Shp-1, has been identified as a modulator of EGF-mediated activation of RTK signaling (15, 33). However, unlike Shp-2, the NF1 protein acts as a negative regulator of Ras signaling, and loss of NF1 function leads to benign neurofibromas, leukemias, and heart valve disease. NF1 directly affects the activation of Ras through enhancing the Ras GTPase activity, thereby maintaining Ras in an inactive GDP-bound state (23). The NF1 protein contains a conserved GTPase-activating domain that is present in other GAPs, and expression of this domain is sufficient to restore normal growth and MAPK activation to nf1–/– cells in culture (23). Increased EGF signaling, Ras activation, and MAPK phosphorylation have been reported for human NF1–/– nerve tumor cells as well as a mouse model of nf1-deficient tumors (15, 33). The loss of NF1 results in disease phenotypes in very specific tissues, including the developing heart valves, which appear to be related to increased Ras activation. However, there are many organ systems that are apparently unaffected by loss of NF1, and this restriction likely reflects yet uncharacterized temporal and spatial limits on NF1 modulation of Ras signal transduction.
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Altered Shp-2 or NF1 Function Leads to Related Valve Malformations in Mice
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Complete LOF of ptpn11 in mice proved relatively uninformative because of early embryonic lethality in the homozygous animals at E8.5–E10.5 due to gastrulation defects (56). Subsequently, D61G, an NS-causing mutation that exhibits increased phosphatase activity (GOF) was modeled in mice using targeted gene modification (2). Although the mutant Shp-2 allele was expressed ubiquitously, tissue-specific phenotypes were observed. D61G lies at the interacting face between the amino-terminal SH2 and phosphatase domains. Homozygous embryos containing the targeted mutation did not survive to birth and exhibited severe cardiac valvu-loseptal defects at E13.5. The heterozygotes survived, although they also showed decreased viability. However, the surviving mice displayed the craniofacial abnormalities characteristic of NS patients and multiple cardiac defects, including AV septal defects, thinning of the ventricular wall, and, strikingly, enlargement of the AV and OFT valves. Enhanced cell proliferation and decreased apoptotic remodeling was observed in the endocardial cushions. These gene-targeted mice displayed some traits that were strikingly similar to mice in which nf1 was ablated (6).
In vitro biochemical analyses of the D61G Shp-2 protein demonstrated increased basal enzymatic activity seven- to eightfold higher than the normal protein in the absence of the activating ligand (2). This effect was mirrored in the mice expressing D61G, which showed approximately a threefold increase in phosphatase activity. The mutant Shp-2 also showed enhanced association with GAB1, similar to the effects observed previously (18). To determine the pattern of downstream signaling resulting from mutant Shp-2 expression, ERK activation was examined using antibodies that recognized the active phosphorylated form. Despite the widespread expression of activated Shp-2, activated ERK was only found in a cell context and cell type-specific pattern where developmental abnormalities subsequently presented, including the developing face region and limb buds. Increased phospho-ERK was also present in the endocardial cushion cells, although those increases were highly variable, consistent with the variable penetrance observed in mouse models and human patients.
Studies of nf1 LOF in mice showed that the homozygous knockout resulted in embryonic lethality due to cardiovascular abnormalities (6). nf1 expression is widespread in the developing embryo; in the developing heart, expression can be detected at E10.5 in the endocardial cushions and in the OFT with only weak expression in the myocardium (32). In mice lacking nf1, severe defects in cardiac cushion formation and valvulo-genesis are apparent, with increased proliferation, decreased apoptosis, and limited remodeling of both AV and OFT cushions at E13.5 (32). The tissue-specific requirements for NF1 were examined via gene ablation targeted specifically to endothelial cells using tie2-driven expression of the recombinase Cre (21). Importantly, the multiple cardiac abnormalities that were also present in the systemically ablated animals, including enlarged endocardial cushions, presented in these animals as well, showing that NF1 expression in the endothelial cells at this developmental time participates in the control of cardiac cushion proliferation. The increased activated Ras detected in embryos lacking endothelial expression of NF1 is consistent with NF1 inhibition of Ras activity in this cell layer and its derivatives. Localization of activated ERK in mouse as well as avian valve endothelial cells was consistent with MAPK activation downstream of Ras in these cells (21, 34). In addition, increased activated ERK was observed in endocardial cushions lacking NF1 (21). The ligands and receptors upstream of NF1 function in heart valve development have not been identified, but the EGF signaling pathway has been implicated in NF1-related tumorigenesis in mice (33). The function of both NF1 and Shp-2 in modulating EGF signaling through Ras and MAPK activation could underlie the common cardiac valve malformations observed in NS and NF1 (Table 2).
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Ras-Related Signaling in Heart Valve Development: Lessons from Animal Models
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Numerous studies in multiple systems point to the importance of Shp-2 and NF1 function in EGF pathway signaling. Analysis of EGF-family ligands and receptors through targeted-mutagenesis studies in mice provided further support for the contribution of altered EGF signaling to NS valve phenotypes (Table 2). Of the EGF family of ligands, heparin binding (HB)-EGF seems to be the most important for this process, as no abnormalities in valve development were observed with loss of the related ligands EGF, ampiregulin, or TGF-
, whereas targeted mutation of hb-egf leads to enlarged, malformed semilunar and AV valves in neonatal animals (10, 27, 28). In E14.5 embryos lacking HB-EGF, increased endocardial cushion size and cell proliferation were observed in both AV and semilunar valves, but earlier stages of endocardial cushion formation were apparently unaffected. Similar defects in valvulogenesis were observed in embryos homozygous for the Noonan mutation D61G, suggesting that decreased or increased signaling through the pathway promotes valve cell proliferation and inhibits valve elongation/remodeling (2).
The ErbB/EGFR receptors involved in valvulogenesis appear to be different for the AV and semilunar valves. Loss or reduction of EGFR/ErbB1 preferentially affects the semilunar valves, and the egfrwa hypomorphic phenotype is enhanced in heterozygous mice lacking a ptpn11 allele (10, 49). Mice lacking ErbB3 die at midgestation of heart failure with hypoplasia of AV and semilunar valve primordia (16). The reduction in endocardial cushion cells in the erbB3–/– embryos is distinct from the hypercellularity of the cushions in HB-EGF-null embryos and may represent the requirement for an additional EGF-family ligand that signals through the ErbB3 receptor during EMT (8). The dependence of both AV and semilunar valves on ErbB3 is consistent with defects observed in valvulogenesis, with loss of HB-EGF or with the Shp-2 D61G GOF alleles (2, 28). Loss of ErbB2 or ErbB4 affects myocardial trabeculation related to neuregulin signaling but does not affect cushion formation directly (16, 20). Therefore, the upstream RTK regulators of Shp-2 signaling in heart valvulogenesis are likely HB-EGF acting through EGFR in the semilunar valves and through ErbB3 in both sets of valves.
Alterations in Ras-related signaling pathways affect the proliferation of heart valve progenitor cells and the remodeling of the valve primordia. Once the endocardial cushions are established, ectopic expression of activated Ras or loss of NF1 results in increased cushion proliferation and migration in culture. NF1 LOF can be overcome with expression of dominant negative Ras (32). Similarly, expression of an NS Shp-2 Q79R protein with GOF results in increased proliferation and migration of chick embryo endocardial cushion mesenchyme, which is abrogated by MAPK inhibition via expression of dominant negative MEK1 (30). These in vitro studies, taken together with genetic analyses in mice, provide evidence for the importance of Ras pathway signaling in the regulation of proliferation and migration of valve progenitor cells. Further manipulation of this pathway in endocardial cushion cultures demonstrated that activated Ras is modulated by Shp-2 and NF1 and leads to activation of MAPK. Therefore, altered Ras signaling appears to lead to defects in the transition from proliferative expansion to elongation and remodeling of the valve primordia, although this has not been demonstrated unequivocally. It seems likely that the observed abnormalities in heart valve progenitor proliferation and remodeling with altered Ras signaling leads directly to the congenital valve defects associated with NS and NF1.
Analyses in mice with decreased HB-EGF signaling or loss of NF1 have provided evidence for the intersection of Ras pathways with other signaling pathways critical for normal heart valve formation. In mice lacking HB-EGF, increased proliferation of valve primordia is accompanied by prolonged Smad1/5/8 phosphorylation, indicative of increased BMP signaling (28). In addition, loss of phospholipase C-
, a downstream effector of EGF and Ras signaling, also results in increased Smad1/5/8 phosphorylation and enlarged semilunar valves in mice (50). Previous studies in developing cartilage and cultured cells have demonstrated an antagonistic relationship between EGF and BMP signaling mechanisms through the regulation of Smad1 phosphorylation (31, 41). Further support for the requirement of BMP inhibition in initiation of valve elongation and remodeling is provided by examination of mice lacking the inhibitory Smad6. These animals exhibit increased valve cell proliferation and lack of remodeling similar to the HB-EGF mutant mice (19, 28). An additional signaling molecule affected by increased Ras signaling in NF1 mutant mice is NFATc1, a transcription factor regulated by calcineurin activation, which is required for maturation of the heart valve primordia (12, 21, 46). However, NFATc1 is not required for EMT, because the early stages of endocardial cushion formation are apparently normal in nfatc1-null mice. In NF1 mutant mice and in cultured cells expressing constitutively active Ras, increased nuclear localization of NFATc1 in endocardial endothelial cells was observed, consistent with a positive role in regulating valve cell proliferation (21). Further support for a proliferative function for NFATc1 is provided by the reduced size of the valve primordia in mice lacking NFATc1 and in the reduced proliferation of cultured human valve endothelium with inhibition of NFATc1 activation (9, 12, 29, 46). Together these studies provide evidence for complex signaling networks that intersect with the Ras pathway in the regulation of heart valve cell proliferation, elongation, and remodeling events. How these pathways intersect, interact, synergize, and/or antagonize one another is just beginning to be appreciated but remains largely undefined.
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Moving Forward
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The limited progress made to date underscores the value of defining the signaling pathways that underlie and function during valve development, but progress in translating these data into the treatment of congenital heart disease in general and valve disease in particular has been frustratingly slow. There are multiple reasons for this. First, investigators and clinician-scientists with the requisite skills in and across the disparate disciplines are few. Second, there is the difficulty in translating basic pathways that have been defined in a genetically amenable system to human physiology. Finally, it is clear that under most conditions, the actual biological signals being transduced are a result of multiple pathway interactions that may both oppose and reinforce one another, and these interactions are modulated depending upon the developmental time and cell-specific contexts. For example, we still do not understand the relevant substrate or substrates that the GOF Shp-2 phosphatase acts upon during valve development. With rare exceptions, we currently lack the algorithms necessary to decipher these multifactorial processes in a way that is useful to the clinician or physiologist. Only by understanding how these multiple pathways intersect will we be able to identify and begin to exploit the potential therapeutic targets for impacting on the causes of congenital heart disease.
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Valve Development and Congenital...
Ras-Related Signaling Pathways...
