Biomedical subjects

Jerry Ware

Publications and source records attributed to Jerry Ware.

At least 19 recordsLinked to original sources

PubMed2006

GPVI potentiation of platelet activation by thrombin and adhesion molecules independent of Src kinases and Syk.

OBJECTIVE: The present study investigates the role of Src and Syk tyrosine kinases in signaling by G-protein coupled and platelet adhesion receptors. METHODS AND RESULTS: Using Syk-/- platelets or the Src kinase inhibitor PP2, we demonstrate a critical role for Src and Syk kinases in mediating lamellipodia formation on VWF, collagen, CRP, fibrinogen, and fibronectin. In all cases, the spreading defect was overcome by addition of thrombin. Conversely, platelet aggregation and alphaIIb beta3 activation induced by thrombin was similar to controls, arguing against a functional role for Src and Syk in alphaIIb beta3 activation. Unexpectedly, CRP potentiated integrin alphaIIb beta3 activation and platelet aggregation induced by subthreshold concentrations of thrombin in Syk-/- platelets or in the presence of the Src kinase inhibitor PP2. Potentiation in the presence of PP2 was lost in the absence of FcRgamma-chain or GPVI confirming that it was mediated through the immunoglobulin receptor. Further delineation of this PP2-resistant synergy revealed that PAR4 could trigger the enhanced response in combination with CRP. CONCLUSIONS: We show that Syk is critical for lamellipodia formation on a range of immobilized proteins but that this can be overcome by addition of thrombin. Further, we reveal a novel role for GPVI in supporting thrombin-induced activation, independent of Syk and Src kinases.

Animals↗

PubMed2006

The role of platelet adhesion receptor GPIbalpha far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis.

GPIbalpha binding to von Willebrand factor (VWF) exposed at a site of vascular injury is thought to be the first step in the formation of a hemostatic plug. However, our previous studies in VWF-deficient mice demonstrated delayed but not absent arterial thrombus formation, suggesting that, under these conditions, GPIbalpha may bind other ligands or that a receptor other than GPIbalpha can mediate platelet adhesion. Here, we studied thrombus formation in transgenic mice expressing GPIbalpha in which the extracellular domain was replaced by that of the human IL-4 receptor (IL4Ralpha/GPIbalpha-tg mice). Platelet adhesion to ferric chloride-treated mesenteric arterioles in IL4Ralpha/GPIbalpha-tg mice was virtually absent in contrast to avid adhesion in WT mice. As a consequence, arterial thrombus formation was inhibited completely in the mutant mice. Our studies further show that, when infused into WT recipient mice, IL4Ralpha/GPIbalpha-tg platelets or WT platelets lacking the 45-kDa N-terminal domain of GPIbalpha failed to incorporate into growing arterial thrombi, even if the platelets were activated before infusion. Surprisingly, platelets lacking beta3 integrins, which are unable to form thrombi on their own, incorporated efficiently into WT thrombi. Our studies provide in vivo evidence that GPIbalpha absolutely is required for recruitment of platelets to both exposed subendothelium and thrombi under arterial flow conditions. Thus, GPIbalpha contributes to arterial thrombosis by important adhesion mechanisms independent of the binding to VWF.

Animals↗

PubMed2006

Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage.

Platelets contain both pro- and antiangiogenic factors, but their regulatory role in angiogenesis is poorly understood. Although previous studies showed that platelets stimulate angiogenesis in vitro, the role of platelets in angiogenesis in vivo is largely uncharacterized. To address this topic, we used two in vivo approaches, the cornea micropocket assay and the Matrigel model, in four animal models: thrombocytopenic, Lyst(bg) (platelet storage pool deficiency), glycoprotein (GP) Ibalpha/IL4R transgenic (lacking extracellular GPIbalpha, the receptor for von Willebrand factor as well as other adhesive and procoagulant proteins), and FcgammaR(-/-) (lacking functional GPVI, the collagen receptor) mice. Adult mice were rendered thrombocytopenic by i.p. administration of an antiplatelet antibody. The number of growing vessels in the thrombocytopenic mice was lower in the cornea assay, and they showed significantly increased appearance of hemorrhage compared with mice treated with control IgG. The thrombocytopenic mice also showed more protein leakage and developed hematomas in the Matrigel model. GPIbalpha/IL4R transgenic mice presented increased hemorrhage in both assays, but it was less severe than in the platelet-depleted mice. FcgammaR(-/-) and Lyst(bg) mice showed no defect in experimental angiogenesis. Intravital microscopy revealed a >3-fold increase in platelet adhesion to angiogenic vessels of Matrigel compared with mature quiescent skin vessels. Our results suggest that the presence of platelets not only stimulates angiogenic vessel growth but also plays a critical role in preventing hemorrhage from the angiogenic vessels. The adhesion function of platelets, as mediated by GPIbalpha, significantly contributes to the process.

Animals↗

PubMed2004

Human septin-septin interactions as a prerequisite for targeting septin complexes in the cytosol.

Septins are a cytosolic GTP-binding protein family first characterized in yeast, but gaining increasing recognition as critical protagonists in higher eukaryotic cellular events. Mammalian septins have been associated with cytokinesis and exocytosis, along with contributing to the development of neurological disorders. Ten different septins, divided into four groups, have been identified in mammals, and individual septins are capable of interacting with each other to form macromolecular complexes. The present study characterizes the structural requirements for human septin-septin interactions using a yeast two-hybrid system. We focus on three septins that are highly expressed in platelets and neurons, SEPT4 [previously designated H5, CDCrel-2 (cell-division-control-related-2), PNUTL2], SEPT5 (CDCrel-1, PNUTL1) and SEPT8 (KIAA0202). Each of these three septins contains a characteristic domain structure consisting of unique N- and C-termini, and a central core domain conserved among the family of proteins. The yeast two-hybrid system yielded data consistent with a model where each of the three septins can interact with itself (homotypic assembly) or with one of the other septins (heterotypic assembly). For SEPT5 and SEPT8, the results illustrate a model whereby heterotypic septin assembly is dependent on the conserved central core domain and homotypic interactions require the N- and C-termini of each protein. We also characterized a model in which the proper cellular localization of SEPT5 and SEPT8 requires concomitant expression of both proteins. Co-transfection of SEPT5 and SEPT8 results in both proteins targeted to a vesicular-like location. Therefore the cellular repertoire of human septins has an impact on function by targeting septin macromolecular complexes to specific cellular locations.

Amino Acid Sequence↗

PubMed2004

Megakaryocyte proliferation and ploidy regulated by the cytoplasmic tail of glycoprotein Ibalpha.

We have investigated the ability of glycoprotein (GP) Ibalpha, a megakaryocytic gene product, to sequester the signal transduction protein 14-3-3xi and to influence megakaryocytopoiesis. Using a Gp1ba(-/-) mouse colony, we compared the rescued phenotypes produced by a wild-type human GP Ibalpha allele or a similar allele containing a 6-residue cytoplasmic tail truncation that abrogates binding to 14-3-3xi. The observed phenotypes illustrate an involvement for GP Ibalpha in thrombopoietin-mediated events of megakaryocyte proliferation, polyploidization, and the expression of apoptotic markers in maturing megakaryocytes. We developed a hypothesis for the involvement of a GP Ibalpha/14-3-3xi/PI-3 kinase complex in regulating thrombopoietin-mediated responses. An observed increase in thrombopoietin-mediated Akt phosphorylation in the truncated variant supported the hypothesis and led to the development of a model in which the GP Ibalpha cytoplasmic tail sequestered signaling proteins during megakaryocytopoiesis and, as such, became a critical regulator in the temporal sequence of events that led to normal megakaryocyte maturation.

14-3-3 Proteins↗

PubMed2004

Genetic deletion of mouse platelet glycoprotein Ibbeta produces a Bernard-Soulier phenotype with increased alpha-granule size.

Here we report the characterization of a mouse model of the Bernard-Soulier syndrome generated by a targeted disruption of the gene encoding the glycoprotein (GP) Ibbeta subunit of the GP Ib-IX complex. Similar to a Bernard-Soulier model generated by disruption of the mouse GP Ibalpha subunit, GP Ibbeta(Null) mice display macrothrombocytopenia and a severe bleeding phenotype. When examined by transmission electron microscopy, the large platelets produced by a GP Ibbeta(Null) genotype revealed alpha-granules with increased size as compared with the alpha-granules from control mouse platelets. Data are presented linking the overexpression of a septin protein, SEPT5, to the presence of larger alpha-granules in the GP Ibbeta(Null) platelet. The SEPT5 gene resides approximately 250 nucleotides 5' to the GP Ibbeta gene and has been associated with modulating exocytosis from neurons and platelets as part of a presynaptic protein complex. Fusion mRNA transcripts present in megakaryocytes can contain both the SEPT5 and GP Ibbeta coding sequences as a result in an imperfect polyadenylation signal within the 3' end of both the human and mouse SEPT5 genes. We observed a 2- to 3-fold increase in SEPT5 protein levels in platelets from GP Ibbeta(Null) mice. These results implicate SEPT5 levels in the maintenance of normal alpha-granule size and may explain the variant granules associated with human GP Ibbeta mutations and the Bernard-Soulier syndrome.

Animals↗

PubMed2004

Dysfunctional platelet membrane receptors: from humans to mice.

Insights into hemostasis and thrombosis have historically benefited from the astute diagnosis of human bleeding and thrombotic disorders followed by decades of careful biochemical characterization. This work has set the stage for the development of a number of mouse models of hemostasis and thrombosis generated by gene targeting strategies in the mouse genome. The utility of these models is the in depth analysis that can be performed on the precise molecular interactions that support hemostasis and thrombosis along with efficacy testing of various therapeutic strategies. Already the mouse has proven to be an excellent model of the processes that support hemostasis and thrombosis in the human vasculature. A brief summary of the salient phenotypes from knockout mice missing key platelet receptors is presented, including the glycoprotein (GP) Ib-IX-V and GP IIb/IIIa (alphaIIb/beta3) receptors; the collagen receptors, GP VI and alpha2/beta1; the protease activated receptors (PARs); and the purinergic receptors, P2Y(1) and P2Y(12). A few differences exist between mouse and human platelets and where appropriate those will be highlighted in this review. Concluding remarks focus on the importance of understanding the power and limitations of various in vitro, ex vivo and in vivo models currently being used and the impact of the mouse strain on the described platelet phenotype.

Animals↗

PubMed2004

Mammalian septin function in hemostasis and beyond.

Interest in the biology of mammalian septin proteins has undergone a birth in recent years. Originally identified as critical for yeast budding throughout the 1970s, the septin family is now recognized to extend from yeast to humans and is associated with a variety of events ranging from cytokinesis to vesicle trafficking. An emerging theme for septins is their presence at sites where active membrane or cytoplasmic partitioning is occurring. Here, we briefly review the mammalian septin protein family and focus on a prototypic human and mouse septin, termed SEPT5, that is expressed in the brain, heart, and megakaryocytes. Work from neurobiology laboratories has linked SEPT5 to the exocytic complex of neurons, with implications that SEPT5 regulates neurotransmitter release. Striking similarities exist between neurotransmitter release and the platelet-release reaction, which is a critical step in platelet response to vascular injury. Work from our laboratory has characterized the platelet phenotype from mice containing a targeted deletion of SEPT5. Most strikingly, platelets from SEPT5(null) animals aggregate and release granular contents in response to subthreshold levels of agonists. Thus, the characterization of a SEPT5-deficient mouse has linked SEPT5 to the platelet exocytic process and, as such, illustrates it as an important protein for regulating platelet function. Recent data suggest that platelets contain a wide repertoire of different septin proteins and assemble to form macromolecular septin complexes. The mouse platelet provides an experimental framework to define septin function in hemostasis, with implications for neurobiology and beyond.

Animals↗

PubMed2004

A sensitive ristocetin co-factor activity assay with recombinant glycoprotein Ibalpha for the diagnosis of patients with low von Willebrand factor levels.

BACKGROUND AND OBJECTIVES: The assay of ristocetin co-factor activity of von Willebrand factor (VWF:RCo) is used in the screening of patients with suspected von Willebrand's disease (VWD), the most frequent inherited bleeding disorder. A correct diagnosis of VWD relies on platelet agglutination tests that have a low accuracy within and between assays. A more accurate VWF:RCo assay would improve VWD diagnosis and classification. DESIGN AND METHODS: We describe here an ELISA method in which a recombinant fragment of the alpha-subunit of platelet glycoprotein Ib-IX-V complex (rGPIbalpha) is bound to an anti-GPIbalpha monoclonal antibody immobilized onto microtiter plate wells and which captures plasma VWF in the presence of ristocetin. The results obtained with this ELISA assay were compared blindly with values calculated from the agglutination test in normal subjects (n=60) and in type 1 (n=8), type 2A (n=16), type 2B (n=13), type 2M (n=17) or type 2M Vicenza (n=8) VWD patients which were characterized by low VWF levels. RESULTS: The two assays gave similar results in both normal subjects and VWD patients (r=0.93), but the ELISA test showed higher sensitivity (0.1 versus 6.25 U/dL). The repeatability and reproducibility gave coefficients of variation of 9% and 10%, respectively, for the ELISA, as compared to 14% and 15% for the agglutination test. INTERPRETATION AND CONCLUSIONS: This ELISA assay can be useful in the identification and classification of VWD patients in that it may provide a more accurate distinction between type 2 with abnormal VWF function and type 1 with a low plasma VWF concentration.

Agglutination Tests↗

PubMed2003

Modulation of alpha-thrombin function by distinct interactions with platelet glycoprotein Ibalpha.

Thrombin bound to platelets contributes to stop bleeding and, in pathological conditions, may cause vascular thrombosis. We have determined the structure of platelet glycoprotein Ibalpha (GpIbalpha) bound to thrombin at 2.3 angstrom resolution and defined two sites in GpIbalpha that bind to exosite II and exosite I of two distinct alpha-thrombin molecules, respectively. GpIbalpha occupancy may be sequential, as the site binding to alpha-thrombin exosite I appears to be cryptic in the unoccupied receptor but exposed when a first thrombin molecule is bound through exosite II. These interactions may modulate alpha-thrombin function by mediating GpIbalpha clustering and cleavage of protease-activated receptors, which promote platelet activation, while limiting fibrinogen clotting through blockade of exosite I.

Binding Sites↗

PubMed2003

The contribution of glycoprotein VI to stable platelet adhesion and thrombus formation illustrated by targeted gene deletion.

Platelet interaction with exposed adhesive ligands at sites of vascular injury is required to initiate a normal hemostatic response and may become a pathogenic factor in arterial diseases leading to thrombosis. We report a targeted disruption in a key receptor for collagen-induced platelet activation, glycoprotein (GP) VI. The breeding of mice with heterozygous GP VI alleles produced the expected frequency of wild-type, heterozygous, and homozygous genotypes, indicating that these animals had no reproductive problems and normal viability. GP VInull platelets failed to aggregate in response to type I fibrillar collagen or convulxin, a snake venom protein and known platelet agonist of GP VI. Nevertheless, tail bleeding time measurements revealed no severe bleeding tendency as a consequence of GP VI deficiency. Ex vivo platelet thrombus formation on type I collagen fibrils was abolished using blood from either GP VInull or FcR-gammanull animals. Reflection interference contrast microscopy revealed that the lack of thrombus formation by GP VInull platelets could be linked to a defective platelet activation following normal initial tethering to the surface, visualized as lack of spreading and less stable adhesion. These results illustrate the role of GP VI in postadhesion events leading to the development of platelet thrombi on collagen fibrils.

Animals↗

PubMed2003

Molecular bases of defective signal transduction in the platelet P2Y12 receptor of a patient with congenital bleeding.

We have identified structural attributes required for signal transduction through a seven-transmembrane-domain receptor. Platelets from a patient (AC) with a congenital bleeding disorder had normal shape change but reduced and reversible aggregation in response to 4 microM ADP, similar to normal platelets with blocked P2Y(12) receptor. The response to 20 microM ADP, albeit still decreased, was more pronounced and was reduced by a P2Y(12) antagonist, indicating some residual receptor function. ADP failed to lower the adenylyl cyclase activity stimulated by prostaglandin E(1) in the patient's platelets, even though the number and affinity of 2-methylthioadenosine 5'-[(33)P]diphosphate-binding sites was normal. Analysis of the patient's P2Y(12) gene revealed a G-to-A transition in one allele, changing the codon for Arg-256 in the sixth transmembrane domain to Gln, and a C-to-T transition in the other allele, changing the codon for Arg-265 in the third extracellular loop to Trp. Neither mutation interfered with receptor surface expression but both altered function, since ADP inhibited the forskolin-induced increase of cAMP markedly less in cells transfected with either mutant P2Y(12) as compared with wild-type receptor. These studies delineate a region of P2Y(12) required for normal function after ADP binding.

Adult↗

PubMed2002

Amelioration of the macrothrombocytopenia associated with the murine Bernard-Soulier syndrome.

An absent platelet glycoprotein (GP) Ib-IX receptor results in the Bernard-Soulier syndrome and is characterized by severe bleeding and the laboratory presentation of macrothrombocytopenia. Although the macrothrombocytopenic phenotype is directly linked to an absent GP Ib-IX complex, the disrupted molecular mechanisms that produce the macrothrombocytopenia are unknown. We have utilized a mouse model of the Bernard-Soulier syndrome to engineer platelets expressing an alpha-subunit of GP Ib (GP Ibalpha) in which most of the extracytoplasmic sequence has been replaced by an isolated domain of the alpha-subunit of the human interleukin-4 receptor (IL-4Ralpha). The IL-4Ralpha/GP Ibalpha fusion is membrane expressed in Chinese hamster ovary (CHO) cells, and its expression is facilitated by the presence of human GP IX and the beta-subunit of GP Ib. Transgenic animals expressing a chimeric receptor were generated and bred into the murine Bernard-Soulier syndrome-producing animals devoid of mouse GP Ibalpha but expressing the IL-4Ralpha/GP Ibalpha fusion sequence. The characterization of these mice revealed a 2-fold increase in circulating platelet count and a 50% reduction in platelet size when compared with platelets from the mouse model of the Bernard-Soulier syndrome. Immunoprecipitation confirmed that the IL-4Ralpha/GP Ibalpha subunit interacts with filamin-1 and 14-3-3zeta, known binding proteins to the GP Ibalpha cytoplasmic tail. Mice expressing the chimeric receptor retain a severe bleeding phenotype, confirming a critical role for the GP Ibalpha extracytoplasmic domain in hemostasis. These results provide in vivo insights into the structural elements of the GP Ibalpha subunit that contribute to normal megakaryocyte maturation and thrombopoiesis.

Animals↗

PubMed2002

A prototypic platelet septin and its participation in secretion.

Studies are presented characterizing platelet CDCrel-1, a protein expressed to high levels by megakaryocytes and belonging to a family of conserved proteins, termed septin. Septin filaments originally were identified in yeast as essential for budding but have become increasingly associated with processes in higher eukaryotic cells involving active membrane movement such as cytokinesis and vesicle trafficking. Direct proof of an in vivo function for septins in higher eukaryotes is limited to the characterization of the Drosophila septin, termed PNUT. We present studies identifying platelet CDCrel-1 as a protein kinase substrate in the presence of known platelet agonists. The immunopurification of CDCrel-1 revealed it to be part of a macromolecular complex containing a protein involved in platelet secretion, syntaxin 4. Moreover, CDCrel-1 was localized in situ to areas surrounding platelet-storage granules. The relevance of CDCrel-1 to normal platelet function was established with the characterization of platelets from a CDCrel-1(Null) mouse. As compared with platelets from wild-type littermates, CDCrel-1(Null) platelets aggregate and release stored [14C]serotonin in the presence of subthreshold levels of collagen. These results provide new insights into the mechanisms regulating platelet secretion and identify platelet septins as a protein family contributing to membrane trafficking within the megakaryocyte and platelet.

Amino Acid Sequence↗

PubMed2002

Lateral clustering of platelet GP Ib-IX complexes leads to up-regulation of the adhesive function of integrin alpha IIbbeta 3.

Binding of von Willebrand factor (VWF) to GP Ib-IX mediates initial platelet adhesion and increases the subsequent adhesive function of alpha(IIb)beta(3). Because these responses are promoted most effectively by large VWF multimers, we hypothesized that receptor clustering modulates GP Ib-IX function. To test this, GP IX was fused at its cytoplasmic tail to tandem repeats of FKBP, and GP Ib-IX(FKBP)(2) and alpha(IIb)beta(3) were expressed in Chinese hamster ovary cells. Under flow conditions at wall shear rates of up to 2000 s(-1), GP Ib-IX(FKBP)(2) mediated cell tethering to immobilized VWF, just as in platelets. Conditional oligomerization of GP Ib-IX(FKBP)(2) by AP20187, a cell-permeable FKBP dimerizer, caused a decrease in cell translocation velocities on VWF (p < 0.001). Moreover, clustering of GP Ib-IX(FKBP)(2) by AP20187 led to an increase in alpha(IIb)beta(3) function, manifested under static conditions by increased cell adhesion to fibrinogen (p < 0.01) and under flow by increased stable cell adhesion to VWF (p < 0.04). Clustering of GP Ib-IX(FKBP)(2) also stimulated rapid tyrosine phosphorylation of ectopically expressed Syk, a putative downstream effector of GP Ib-IX in platelets. These studies establish that GP Ib-IX oligomerization, per se, affects the interaction of this receptor with VWF and its ability to influence the adhesive function of alpha(IIb)beta(3). By extrapolation, GP Ib-IX clustering in platelets may promote thrombus formation.

Animals↗

PubMed2002

Absence of GPIbalpha is responsible for aberrant membrane development during megakaryocyte maturation: ultrastructural study using a transgenic model.

OBJECTIVE: The glycoprotein Ib/IX/V complex (GPIb-IX-V) mediates platelet attachment to von Willebrand factor in exposed subendothelium. Molecular defects in the genes for GPIbalpha, GPIbbeta, and GPIX give rise to the Bernard-Soulier syndrome, in which thrombocytopenia and giant platelets suggest that this receptor also is involved in platelet production. To study how giant platelets are produced in vivo, we used a model of GPIbalpha-deficient mice (GPIbalpha(null)) and mice rescued with the human GPIbalpha transgene (GPIbalpha(null;hTg)). MATERIALS AND METHODS: Using electron microscopy and immunogold labeling, we examined megakaryocytopoiesis in the bone marrow of these mice and developed a method to quantify the membranes of megakaryocytes (MK) and proplatelets by computer analysis. RESULTS: Abnormal membrane development in the perinuclear zone was found in immature MK of GPIbalpha(null) mice. This led to a poorly developed demarcation membrane system and other ultrastructural changes. As a result, well-organized platelet territories were rarely seen within the cytoplasm of mature MK. Membrane quantification confirmed that MK of GPIbalpha(null) mice had a reduced internal membrane pool. Whereas these MK normally crossed the endothelial barrier, their migration was accompanied by the production of unusually large MK fragments or proplatelets in the vascular sinus with an approximately 50% decrease in internal membrane content compared to wild-type. In the rescued GPIbalpha(null;hTg) model, GPIbalpha was normally localized in MK, and there was a total correction of the ultrastructural defects. CONCLUSIONS: GPIbalpha is essential for membrane development and distribution in maturing MK. Its absence leads to abnormal partitioning of the membrane systems and abnormal proplatelet production.

Animals↗

PubMed2002

Mammalian septins nomenclature.

There are 10 known mammalian septin genes, some of which produce multiple splice variants. The current nomenclature for the genes and gene products is very confusing, with several different names having been given to the same gene product and distinct names given to splice variants of the same gene. Moreover, some names are based on those of yeast or Drosophila septins that are not the closest homologues. Therefore, we suggest that the mammalian septin field adopt a common nomenclature system, based on that adopted by the Mouse Genomic Nomenclature Committee and accepted by the Human Genome Organization Gene Nomenclature Committee. The human and mouse septin genes will be named SEPT1-SEPT10 and Sept1-Sept10, respectively. Splice variants will be designated by an underscore followed by a lowercase "v" and a number, e.g., SEPT4_v1.

Alternative Splicing↗

PubMed2002

The septin CDCrel-1 is dispensable for normal development and neurotransmitter release.

Septins are GTPases required for the completion of cytokinesis in a variety of organisms, yet their role in this process is not known. Septins may have additional functions since the mammalian septin CDCrel-1 is predominantly expressed in the nervous system, a largely postmitotic tissue. While relatively little is known about the function of this protein, we have previously shown that it is involved in regulated secretion. In addition, the gene encoding this protein maps to a locus often deleted in velo-cardiofacial and DiGeorge syndromes, and CDCrel-1 has recently been shown to be a direct target of the E3 ubiquitin ligase activity of Parkin, a causative agent in autosomal recessive forms of Parkinson's disease. Here we show that CDCrel-1 expression rises at the time of synaptic maturation and that CDCrel-1 is present in a complex that includes the septins Nedd5 and CDC10. To investigate its function in the nervous system, we generated homozygotic CDCrel-1 null mice and showed that these mice appear normal with respect to synaptic properties and hippocampal neuron growth in vitro. Moreover, we found that while the expression of a number of synaptic proteins is not affected in the CDCrel-1 mutant mice, the expression of other septins is altered. Together, these data suggest that CDCrel-1 is not essential for neuronal development or function, and that changes in expression of other septins may account for its functional redundancy.

Animals↗