Search PubMed⌕ Search

Biomedical subjects

C E Henderson

Publications and source records attributed to C E Henderson.

At least 37 records · Page 2Linked to original sources
PubMed1998

Calpain inhibitors, but not caspase inhibitors, prevent actin proteolysis and DNA fragmentation during apoptosis.

Apoptosis, or programmed cell death, involves a cascade of regulatory events leading to the activation of specific proteases. However, the key substrates for these proteases remain to be identified. We previously demonstrated that levels of five unidentified polypeptides were specifically increased in neurons from embryonic chicken ciliary ganglia undergoing apoptosis by trophic deprivation. Here we show by microsequencing of two of these polypeptides that they are fragments of actin. One of them represents cleavage of actin at the site of interaction with DNase I. The same actin fragments are also found at early stages of apoptosis in chicken and rat dorsal root ganglion neurons, chicken spinal motoneurons and rat thymocytes. Actin fragmentation may play a role in the apoptotic process, since calpain inhibitors I and II both inhibit neuronal death and suppress actin fragmentation. In contrast, caspase (ICE family) inhibitors, though effective in delaying neuronal death, do not prevent actin cleavage or DNA fragmentation. These results indicate a key role for calpain-like proteases in neuronal programmed cell death and suggest that actin fragmentation in the cell is correlated with subsequent DNA fragmentation.

Actins↗
PubMed1997

A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor.

Glial-cell-line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent survival factors for sympathetic, sensory and central nervous system neurons. GDNF mediates its actions through a multicomponent receptor system composed of a ligand-binding glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-alpha) and the transmembrane protein tyrosine kinase Ret. In contrast, the mechanism by which the NTN signal is transmitted is not well understood. Here we describe the identification and tissue distribution of a GPI-linked protein (designated NTNR-alpha) that is structurally related to GDNFR-alpha. We further demonstrate that NTNR-alpha binds NTN (K[d] approximately 10 pM) but not GDNF with high affinity; that GDNFR-alpha binds to GDNF but not NTN with high affinity; and that cellular responses to NTN require the presence of NTNR-alpha. Finally, we show that NTN, in the presence of NTNR-alpha, induces tyrosine-phosphorylation of Ret, and that NTN, NTNR-alpha and Ret form a physical complex on the cell surface. These findings identify Ret and NTNR-alpha as signalling and ligand-binding components, respectively, of a receptor for NTN and define a novel family of receptors for neurotrophic and differentiation factors composed of a shared transmembrane protein tyrosine kinase and a ligand-specific GPI-linked protein.

Amino Acid Sequence↗
PubMed1997

Low-affinity nerve growth factor receptor is associated with motoneuron axonal pathways.

The unidentified cell-surface antigen recognized by monoclonal antibody M7412 is distributed along motoneuron axonal outgrowth pathways in chicken embryos. To better characterize its role in motoneuron development, the M7412 antigen was purified from chicken embryos by immunoaffinity chromatography. Its N-terminal amino acid sequence corresponded to that predicted for chicken low-affinity nerve growth factor receptor (LNGFR). Experiments were performed to confirm that LNGFR was indeed the antigen recognized by M7412. First, M7412 bound to recombinant chicken LNGFR expressed in mammalian cells. Second, a rabbit serum raised to the purified antigen showed the same staining pattern in chicken embryos as did M7412. Lastly, a novel method for direct detection of nerve growth factor (NGF) bound to its receptors was used to show that in mixed spinal cord cultures, only neurons that expressed M7412 antigen had low-affinity binding sites for NGF. Furthermore, at the subcellular level, M7412 labeling was co-localized with bound NGF. The M7412 antigen is thus chicken LNGFR, whose role in motoneuron outgrowth pathways is discussed.

Amino Acid Sequence↗
PubMed1997

Motoneuron differentiation, survival and synaptogenesis.

The motoneuron is the central neuron whose development is best understood. Recent research has provided much new information about the molecules involved in aspects of motoneuron development first outlined by classic embryology studies. Over the past year, progress has been particularly apparent in the following areas: motoneuron induction and control of motoneuron identity; factors that guide motor axon outgrowth; neurotrophic factors for motoneurons; and early steps in the formation of the neuromuscular junction.

Animals↗
PubMed1997

Hepatocyte growth factor (HGF/SF) is a muscle-derived survival factor for a subpopulation of embryonic motoneurons.

Muscle-derived factors are known to be important for the survival of developing spinal motoneurons, but the molecules involved have not been characterized. Hepatocyte growth factor/scatter factor (HGF/SF) plays an important role in muscle development and motoneuron axon outgrowth. We show that HGF/SF has potent neurotrophic activity (EC50=2 pM) for a subpopulation (40%) of purified embryonic rat motoneurons. Moreover, HGF/SF is an essential component of muscle-derived support for motoneurons, since blocking antibodies to HGF/SF specifically inhibited 65% of the trophic activity of media conditioned by C2/C7 skeletal myotubes, but did not inhibit the trophic activity secreted by Schwann cell lines. High levels of expression of the HGF/SF receptor c-Met in the spinal cord are restricted to subsets of motoneurons, mainly in limb-innervating segments. Consistent with this distribution, cultured motoneurons from limb-innervating brachial and lumbar segments showed a more potent response to HGF/SF than did thoracic motoneurons. By the end of the period of motoneuron cell death, levels of c-Met mRNA in motoneurons were markedly reduced, suggesting that the effects of HGF/SF may be limited to the period of motoneuron cell death. HGF/SF may play an important role during motoneuron development as a muscle-derived survival factor for a subpopulation of limb-innervating motoneurons.

Animals↗
PubMed1996

Characterization of a multicomponent receptor for GDNF.

Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for central and peripheral neurons, and is essential for the development of kidneys and the enteric nervous system. Despite the potential clinical and physiological importance of GDNF, its mechanism of action is unknown. Here we show that physiological responses to GDNF require the presence of a novel glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-alpha) that is expressed on GDNF-responsive cells and binds GDNF with a high affinity. We further demonstrate that GDNF promotes the formation of a physical complex between GDNFR-alpha and the orphan tyrosin kinase receptor Ret, thereby inducing its tyrosine phosphorylation. These findings support the hypothesis that GDNF uses a multi-subunit receptor system in which GDNFR-alpha and Ret function as the ligand-binding and signalling components, respectively.

Amino Acid Sequence↗
PubMed1996

Transforming growth factor-beta 3, glial cell line-derived neurotrophic factor, and fibroblast growth factor-2, act in different manners to promote motoneuron survival in vitro.

Developing chick motoneurons depend on as yet unidentified factors from the periphery and the central nervous system for their survival. Using cultures of purified embryonic motoneurons, we show that basic fibroblast growth factor (FGF-2) or transforming growth factor-beta 3 (TGF beta 3) each have only low survival-promoting activity when tested alone, but act synergistically to keep motoneurons alive for at least 3 days. Glial cell line-derived neurotrophic factor (GDNF), another member of the TGF beta family, was itself sufficient to maintain a population of motoneurons. However, its effect was not significantly increased by the addition of FGF-2. These results suggest that FGF-2, TGF beta 3, and GDNF, which are all present in the environment of developing motoneurons, may act different mechanisms as physiological survival factors for this population of central neurons.

Animals↗
PubMed1996

Cardiotrophin-1, a cytokine present in embryonic muscle, supports long-term survival of spinal motoneurons.

The muscle-derived factors required for survival of embryonic motoneurons are not clearly identified. Cardiotrophin-1 (CT-1), a cytokine related to ciliary neurotrophic factor (CNTF), is expressed at high levels in embryonic limb bud and is secreted by differentiated myotubes. In vitro, CT-1 kept 43% of purified E14 rat motoneurons alive for 2 weeks (EC50 = 20 pM). In vivo, CT-1 protected neonatal sciatic motoneurons against the effects of axotomy. CT-1 action on motoneurons was inhibited by phosphatidylinositol-specific phospholipase C (PIPLC), suggesting that CT-1 may act through a GPI-linked component. Since no binding of CT-1 to CNTFR alpha was detected, CT-1 may use a novel cytokine receptor alpha subunit. CT-1 may be important in normal motoneuron development and as a potential tool for slowing motoneuron degeneration in human diseases.

Animals↗
PubMed1996

Role of neurotrophic factors in neuronal development.

The spectrum of potential biological roles for neurotrophic factors in development and maturation of the nervous system continues to widen. Careful analysis of the phenotypes of knock-out mice has been used to test directly the 'neurotrophic hypothesis', and the role of members of the transforming growth factor beta superfamily--in particular, glial cell line derived neurotrophic factor--in regulating neuronal survival has become apparent. The effects of neurotrophin-3 on early neuronal differentiation and maturation have proved to be both multiple and complex. Neurotrophic factors are also emerging as potential regulators of synapse stabilization and function.

Animals↗
PubMed1995

Longitudinal measurement of amniotic fluid index in postterm pregnancies and its association with fetal outcome.

OBJECTIVE: Our purpose was to study the association between dynamic changes in serial amniotic fluid index measurements and adverse fetal outcome in postterm pregnancies. STUDY DESIGN: Serial amniotic fluid index values were obtained semiweekly in 139 reliably dated, uncomplicated, singleton pregnancies at > 41 weeks' gestation. Adverse fetal outcome was defined by the presence of moderate or thick meconium, fetal heart rate decelerations, cesarean delivery for fetal distress, neonatal intensive care unit admission, and perinatal mortality. RESULTS: Prominent changes in the amniotic fluid index (i.e., > 50% increase or decrease) had no association with adverse fetal outcome irrespective of rate of change, provided the final value remained > 5.0 cm. A significant association with fetal heart rate decelerations and the presence of meconium was detected only in patients whose final amniotic fluid index was < or = 5.0 cm (p = 0.007 and p = 0.003, respectively). CONCLUSION: Irrespective of the rate of change in amniotic fluid index, postterm pregnancies are significantly associated with potential complications such as fetal heart rate decelerations and meconium staining when the final amniotic fluid index is < or = 5.0 cm.

Amniotic Fluid↗
PubMed1995

The management of a persistent adnexal mass in pregnancy.

OBJECTIVE: Our purpose was to evaluate the pathologic features and outcome of pregnancy complicated by a persistent adnexal mass that was managed conservatively or with surgical intervention. STUDY DESIGN: A review was performed of patients who were seen with an adnexal mass in pregnancy from January 1988 to June 1994. We included patients with simple or complex masses > or = 6 cm that were persistent on ultrasonographic evaluation. We excluded cysts that spontaneously resolved by 16 weeks' gestation and those diagnosed after delivery. RESULTS: Thirty-one patients of 43,372 deliveries were identified with persistent adnexal masses that met the above criteria. Nineteen (59%) of these patients had operative intervention, whereas 12 (41%) were managed conservatively. Of the patients who had surgery, nine had functional cysts, six had mature cystic teratomas, and four had other benign cysts. Complications within 12 hours of surgery included one spontaneous abortion and one patient with rupture of membranes. Twelve patients were managed nonsurgically. Seven patients had conservative management, whereas five patients had percutaneous drainage of simple cysts (negative results on cytologic study) that were symptomatic. CONCLUSIONS: Although the incidence of ovarian cancer in pregnancy is low, the incidental finding of an adnexal mass in pregnancy is becoming more common. Because complications of abdominal surgery are increased in pregnancy, surgical management of this prenatal complication needs to be reconsidered. Our data support a randomized clinical study to determine optimal management of an adnexal mass in pregnancy.

Adnexal Diseases↗
PubMed1995

Embryonic rat motoneurons express a functional P-type voltage-dependent calcium channel.

Only L- and N-type high voltage-activated calcium currents (HVA ICa) have been demonstrated in identified embryonic spinal motoneurons. However, pharmacological experiments suggest that other HVA ICa, including P-type, govern neurotransmitter release at the adult neuromuscular junction. We sought to analyse if embryonic motoneurons express these other ICa, using the whole-cell voltage-clamp method on motoneurons purified by a new metrizamide-panning technique from E15 rat embryos. In addition to L-type dihydropyridine-sensitive and N-type omega-GVIA-sensitive currents, motoneurons express two other HVA ICa. One has properties related to the P-type channel currents described in Purkinje cells: it is inhibited by the peptide omega-agatoxin-IVA with a maximal effect at 100-200 nM. The inhibited current has a characteristic sustained component during depolarizing test pulses. Furthermore, 50-100 nM concentrations of omega-agatoxin-IVA reduce the increase in cytoplasmic calcium concentration observed after depolarization. The other HVA ICa is resistant to saturating concentrations of verapamil, omega-conotoxin GVIA and omega-agatoxin-IVA which block L, N and P-type HVA ICa, respectively. These results suggest that it is now possible to dissect, using a simple method of purification, the properties of the ICa in embryonic mammalian motoneurons and to provide pharmacological evidence for multiple calcium channels which may be involved in regulation of their activity during development.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1995

Assessing the risk of gestational diabetes in twin gestation.

This study examines the hypothesis that twin gestation is a risk factor for gestational diabetes. In a retrospective analysis, the incidence of gestational diabetes in twin and singleton pregnancies was determined in groups matched for maternal age, weight, and parity. One-hour oral glucose challenge tests (50 g) were used to screen 9185 pregnant women. Gestational diabetes was diagnosed when abnormal screens (> or = 130 mg/dL) were followed by two or more abnormal values on a 3-hour (100 g) glucose tolerance test using National Diabetes Data Group (NDDG) criteria. A twin gestation was identified in 1.5% (138/9185) of the pregnancies. Gestational diabetes was diagnosed in 5.8% (8/138) and 5.4% (439/9047) of the twin and singleton pregnancies, respectively. The incidence of gestational diabetes is similar for singleton and twin gestations.

Adult↗
PubMed1995

Survival of newly postmitotic motoneurons is transiently independent of exogenous trophic support.

We compared the survival requirements of early- and late-born motoneurons from E5 chicken spinal cord. Density gradient centrifugation followed by immunopanning using SC1 antibody allowed us to purify two size classes of motoneuron. Large motoneurons retained by 6.8% metrizamide were shown by BrdU labeling in ovo to be born on average 1.5 d earlier than the small motoneurons recovered from the metrizamide pellet. Large motoneurons were both biochemically and functionally more mature: they expressed higher levels of choline acetyltransferase and low-affinity neurotrophin receptor, and had an acute requirement for trophic support from muscle-derived factors. After 24 hr in culture in basal medium, all early-born motoneurons died, whereas 60% of late-born motoneurons survived. Small motoneurons can develop into large motoneurons in ovo, suggesting that they represent a general transitional stage in motoneuron development. Our results suggest that a defined period elapses between birth of a motoneuron and its acquisition of trophic dependence, possibly corresponding to the time required for target innervation. This property may have important consequences for the timing and regulation of developmental motoneuron death.

Animals↗
PubMed1995

Management of tuberculosis in pregnancy.

In the United States, escalating rates of homelessness and human immunodeficiency virus infection have provided a background for the resurgence of Mycobacterium tuberculosis. This scourge of tuberculosis has disproportionately affected groups of reproductive-age women who have limited access to health care. Despite wide reporting of an increased incidence of tuberculosis, a low index of suspicion continues to delay diagnosis of the disease in pregnant women. As a result, a newborn diagnosed with congenital infection often becomes the index case for maternal infection. To become proficient in the prenatal diagnosis of tuberculosis, clinicians must make an in-depth review of the clinical signs and symptoms consistent with tuberculosis a routine part of obstetrical screening. Once diagnosed, tuberculosis is treated as aggressively in pregnancy as it is in the nonpregnant patient.

Female↗
PubMed1994

GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle.

For survival, embryonic motoneurons in vertebrates depend on as yet undefined neurotrophic factors present in the limb bud. Members of the neurotrophin family are currently the best candidates for such neurotrophic factors, but inactivation of their receptor genes leads to only partial loss of motoneurons, which suggests that other factors are involved. Glial cell line-derived neurotrophic factor (GDNF), originally identified as a trophic factor specific for dopaminergic neurons, was found to be 75-fold more potent than the neurotrophins in supporting the survival of purified embryonic rat motoneurons in culture. GDNF messenger RNA was found in the immediate vicinity of motoneurons during the period of cell death in development. In vivo, GDNF rescues and prevents the atrophy of facial motoneurons that have been deprived of target-derived survival factors by axotomy. GDNF may therefore be a physiological trophic factor for spinal motoneurons. Its potency and specificity in vitro and in vivo also make it a good candidate for treatment of motoneuron disease.

Animals↗