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Marie T. Killeen - One of the best experts on this subject based on the ideXlab platform.
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The ENU-3 protein family members function in the Wnt pathway parallel to UNC-6/Netrin to promote motor neuron axon outgrowth in C. elegans.
Developmental biology, 2017Co-Authors: Roxana Oriana Florica, Victoria E. B. Hipolito, Stephen Bautista, Homa Anvari, Chloe Rapp, Suzan El-rass, Alimohammad Asgharian, Costin N. Antonescu, Marie T. KilleenAbstract:The axons of the DA and DB classes of motor neurons fail to reach the dorsal cord in the absence of the guidance cue UNC-6/Netrin or its receptor UNC-5 in C. elegans. However, the axonal processes usually exit their cell bodies in the ventral cord in the absence of both molecules. Strains lacking functional versions of UNC-6 or UNC-5 have a low level of DA and DB motor neuron axon outgrowth defects. We found that mutations in the genes for all six of the ENU-3 proteins function to enhance the outgrowth defects of the DA and DB axons in strains lacking either UNC-6 or UNC-5. A mutation in the gene for the MIG-14/Wntless protein also enhances defects in a strain lacking either UNC-5 or UNC-6, suggesting that the ENU-3 and Wnt pathways function parallel to the Netrin pathway in directing motor neuron axon outgrowth. Our evidence suggests that the ENU-3 proteins are novel members of the Wnt pathway in nematodes. Five of the six members of the ENU-3 family are predicted to be single-pass trans-membrane proteins. The expression pattern of ENU-3.1 was consistent with plasma membrane localization. One family member, ENU-3.6, lacks the predicted signal peptide and the membrane-spanning domain. In HeLa cells ENU-3.6 had a cytoplasmic localization and caused actin dependent processes to appear. We conclude that the ENU-3 family proteins function in a pathway parallel to the UNC-6/Netrin pathway for motor neuron axon outgrowth, most likely in the Wnt pathway.
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ENU 3 functions in an unc 6 netrin dependent pathway parallel to unc 40 dcc frazzled for outgrowth and guidance of the touch receptor neurons in c elegans
Developmental Dynamics, 2014Co-Authors: Callista Yee, Roxana Oriana Florica, Jeffrey Fillingham, Marie T. KilleenAbstract:Background: UNC-6 and SLT-1 guide the migrations of the ventrally directed processes of the AVM and PVM touch receptor neurons and UNC-6 guides the axons of the DA and DB classes of motor neurons in C. elegans. The UNC-6 receptors are UNC-5 and UNC-40. The axon outgrowth defects of a subset of the DB motor neurons in the absence of UNC-5 are enhanced by mutations in ENU-3. Results: An ENU-3 mutation enhances defects in ventral guidance of the processes of the AVM and PVM touch receptor neurons, the dorsal guidance of the distal tip cell and causes additional architectural defects in axons in unc-40 mutant strains in an UNC-6 dependent manner. These observations suggest that ENU-3 and UNC-40 function in parallel pathways dependent on UNC-6. ENU-3 depends on the presence of UNC-40 for its full effect on motor neuron axon outgrowth. Conclusions: ENU-3 works in an UNC-6 dependent pathway parallel to UNC-40 in ventral guidance of AVM and PVM and in dorsal guidance of the distal tip cells. Motor neuron axon outgrowth defects are caused by the presence of UNC-40 and the absence of functional UNC-5 or UNC-6 and defects are enhanced by the absence of functional ENU-3. Developmental Dynamics 243:459–467, 2014. © 2013 Wiley Periodicals, Inc.
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ENU-3 is a novel motor axon outgrowth and guidance protein in C. elegans.
Developmental Biology, 2011Co-Authors: Callista Yee, Stephanie S. Sybingco, Viktoria Serdetchania, Ganna Kholkina, Matthew Bueno De Mesquita, Zafaryab Naqvi, Sang-hyeon Park, Karmen Lam, Marie T. KilleenAbstract:During the development of the nervous system, the migration of many cells and axons is guided by extracellular molecules. These molecules bind to receptors at the tips of the growth cones of migrating axons and trigger intracellular signaling to steer the axons along the correct trajectories. We have identified a novel mutant, ENU-3 (enhancer of Unc), that enhances the motor neuron axon outgrowth defects observed in strains of Caenorhabditis elegans that lack either the UNC-5 receptor or its ligand UNC-6/Netrin. Specifically, the double-mutant strains have enhanced axonal outgrowth defects mainly in DB4, DB5 and DB6 motor neurons. ENU-3 single mutants have weak motor neuron axon migration defects. Both outgrowth defects of double mutants and axon migration defects of ENU-3 mutants were rescued by expression of the H04D03.1 gene product. ENU-3/H04D03.1 encodes a novel predicted putative trans-membrane protein of 204 amino acids. It is a member of a family of highly homologous proteins of previously unknown function in the C. elegans genome. ENU-3 is expressed in the PVT interneuron and is weakly expressed in many cell bodies along the ventral cord, including those of the DA and DB motor neurons. We conclude that ENU-3 is a novel C. elegans protein that affects both motor axon outgrowth and guidance.
Roxana Oriana Florica - One of the best experts on this subject based on the ideXlab platform.
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The ENU-3 protein family members function in the Wnt pathway parallel to UNC-6/Netrin to promote motor neuron axon outgrowth in C. elegans.
Developmental biology, 2017Co-Authors: Roxana Oriana Florica, Victoria E. B. Hipolito, Stephen Bautista, Homa Anvari, Chloe Rapp, Suzan El-rass, Alimohammad Asgharian, Costin N. Antonescu, Marie T. KilleenAbstract:The axons of the DA and DB classes of motor neurons fail to reach the dorsal cord in the absence of the guidance cue UNC-6/Netrin or its receptor UNC-5 in C. elegans. However, the axonal processes usually exit their cell bodies in the ventral cord in the absence of both molecules. Strains lacking functional versions of UNC-6 or UNC-5 have a low level of DA and DB motor neuron axon outgrowth defects. We found that mutations in the genes for all six of the ENU-3 proteins function to enhance the outgrowth defects of the DA and DB axons in strains lacking either UNC-6 or UNC-5. A mutation in the gene for the MIG-14/Wntless protein also enhances defects in a strain lacking either UNC-5 or UNC-6, suggesting that the ENU-3 and Wnt pathways function parallel to the Netrin pathway in directing motor neuron axon outgrowth. Our evidence suggests that the ENU-3 proteins are novel members of the Wnt pathway in nematodes. Five of the six members of the ENU-3 family are predicted to be single-pass trans-membrane proteins. The expression pattern of ENU-3.1 was consistent with plasma membrane localization. One family member, ENU-3.6, lacks the predicted signal peptide and the membrane-spanning domain. In HeLa cells ENU-3.6 had a cytoplasmic localization and caused actin dependent processes to appear. We conclude that the ENU-3 family proteins function in a pathway parallel to the UNC-6/Netrin pathway for motor neuron axon outgrowth, most likely in the Wnt pathway.
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ENU 3 functions in an unc 6 netrin dependent pathway parallel to unc 40 dcc frazzled for outgrowth and guidance of the touch receptor neurons in c elegans
Developmental Dynamics, 2014Co-Authors: Callista Yee, Roxana Oriana Florica, Jeffrey Fillingham, Marie T. KilleenAbstract:Background: UNC-6 and SLT-1 guide the migrations of the ventrally directed processes of the AVM and PVM touch receptor neurons and UNC-6 guides the axons of the DA and DB classes of motor neurons in C. elegans. The UNC-6 receptors are UNC-5 and UNC-40. The axon outgrowth defects of a subset of the DB motor neurons in the absence of UNC-5 are enhanced by mutations in ENU-3. Results: An ENU-3 mutation enhances defects in ventral guidance of the processes of the AVM and PVM touch receptor neurons, the dorsal guidance of the distal tip cell and causes additional architectural defects in axons in unc-40 mutant strains in an UNC-6 dependent manner. These observations suggest that ENU-3 and UNC-40 function in parallel pathways dependent on UNC-6. ENU-3 depends on the presence of UNC-40 for its full effect on motor neuron axon outgrowth. Conclusions: ENU-3 works in an UNC-6 dependent pathway parallel to UNC-40 in ventral guidance of AVM and PVM and in dorsal guidance of the distal tip cells. Motor neuron axon outgrowth defects are caused by the presence of UNC-40 and the absence of functional UNC-5 or UNC-6 and defects are enhanced by the absence of functional ENU-3. Developmental Dynamics 243:459–467, 2014. © 2013 Wiley Periodicals, Inc.
Hiroyuki Nakayama - One of the best experts on this subject based on the ideXlab platform.
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ethylnitrosourea induces neural progenitor cell apoptosis after s phase accumulation in a p53 dependent manner
Neurobiology of Disease, 2005Co-Authors: Keiichi Katayama, Masaki Ueno, Hirofumi Yamauchi, Takayuki Nagata, Hiroyuki NakayamaAbstract:Neural progenitor cells populate the ventricular zone of the fetal central nervous system. In this study, immediately after the administration of ethylnitrosourea (ENU), an alkylating agent, an accumulation of neural progenitor cells in the S phase was observed. This event was caused by the inhibition or arrest of DNA replication rather than acceleration of the G1/S transition. Soon after this accumulation reached its peak, the number of cells in the G2/M phase decreased and the apoptotic cell count increased. In p53-deficient mice, both ENU-induced apoptosis and S-phase accumulation were almost completely abrogated. These findings indicate that ENU inhibits or arrests DNA replication in neural progenitor cells during the S phase and then evokes apoptosis before the cells enter the G2 phase. Furthermore, these data also demonstrate that both ENU-induced apoptosis and cell cycle perturbation in the S phase require p53.
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ethylnitrosourea induces apoptosis and growth arrest in the trophoblastic cells of rat placenta
Biology of Reproduction, 2002Co-Authors: Keiichi Katayama, Katsumi Uetsuka, Masaki Ueno, Hirotake Takai, Noriko Ejiri, Hiroyuki NakayamaAbstract:Ethylnitrosourea (ENU), a well known alkylating agent, induces congenital anomalies in fetuses when it is administered to pregnant animals. In previous studies, we reported that ENU induced apoptosis and growth arrest in fetal tissues and organs immediately after its administration to pregnant rats. In the present study, we investigated the histopathological changes of the placenta after ENU administration to pregnant rats on Day 13 of gestation (GD13) to obtain a clue for clarifying the role of the placenta in the process of fetal developmental disability induced by genotoxic stress. Apoptotic cells increased and DNA-replicating cells decreased in the trophoblastic cells in the placental labyrinth zone of the ENU-treated group by 3 h after treatment. The number of apoptotic cells peaked at 6 h after treatment and returned to control levels at 48 h after treatment. The number of DNA-replicating cells reached minimum levels at 6 h after treatment and returned to control levels at 48 h after treatment. By immunohistochemistry, p53-positive signals were observed in trophoblastic cells in the labyrinth zone of the ENU-treated group from 3 to 6 h after treatment. Significant decreases in fetal and placental weights were observed in the ENU-treated group at 2 days (GD15) and 8 days (GD21) after treatment. A reduction in the thickness of the labyrinth zone was histopathologically significant in the ENU-treated group. These results indicate that ENU induces apoptosis and growth arrest not only in fetal tissues, but also in trophoblastic cells in the rat placental labyrinth zone, and these placental changes may have roles in the induction of fetotoxicity and teratogenicity of ENU. Moreover, a possible involvement of p53 in the induction of apoptosis and growth arrest is suggested.
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ethylnitrosourea induced apoptosis in primordial germ cells of the rat fetus
Experimental and Toxicologic Pathology, 2002Co-Authors: Keiichi Katayama, Masaki Ueno, Hirofumi Yamauchi, Hiroyuki NakayamaAbstract:Summary Ethylnitrosourea (ENU) is a simple alkylating agent. It induces gene mutations in fetal primordial germ cells (PGCs), and a high incidence of congenital malformations is also found in the offspring of male mice treated with ENU at the embryonic stage. It is also reported that decreases in the fertility rate and weights of the testis and ovary were found in the offspring from dams treated with ENU. In this study, we analyzed the occurrence of apoptotic cell death and the expression of p53 protein which is thought to play an important role in the DNA damage-induced apoptosis after administration of ENU to pregnant rats on day 13 of gestation to obtain a clue for clarifying the toxic effect of ENU on PGCs. Apoptotic cells increased in PGCs in fetal gonads from 3 h after treatment. The number of apoptotic PGCs peaked at 6 h and gradually decreased towards 24 h after treatment. On the other hand, p53-positive PGCs increased from 1 h after treatment, prior to the induction of apoptosis. The number of p53-positive PGCs peaked at 3 h and returned to the control level at 24 h after treatment. These results suggest that ENU induces apoptosis in rat fetal PGCs immediately after its administration to dams and excess cell death by apoptosis may have a close relation to the later occurrence of decreases in the fertility rate and gonadal weight. Moreover, a possible involvement of p53 is suggested in the ENU-induced apoptosis in PGCs.
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apoptotic cell death and cell proliferative activity in the rat fetal central nervous system from dams administered with ethylnitrosourea ENU
Histology and Histopathology, 2001Co-Authors: Keiichi Katayama, Katsumi Uetsuka, Noriaki Ishigami, Hiroyuki NakayamaAbstract:Ethylnitrosourea (ENU), a weii known DNA alkylating agent, induces anomalies in the central nervous system (CNS), craniofacial tissues and male reproductive organs, and the enhancement of apoptosis is found in these tissues immediately after the administration of ENU (Katayama et al., 2000a). In this study, pregnant rats were treated with 6Omgikg of ENU at day 13 of gestation, and kinetics of apoptotic cells, mitotic cells and bromodeoxyuridine (BrdU)-positive cells in the fetal CNS were examined from 3 to 48 hours after the treatment (HAT). From 3 HAT, a significant increase in the number of apoptotic cells and a significant decrease in the number of mitotic cells were detected in the fetal CNS, and BrdU-positive cells significantly decreased in accordance with the increase in the number of apoptotic cells. The present results strongly suggest that both excess cell death by apoptosis and cell growth arrest indicated by decreased number of mitotic cells and BrdU-positive cells may have a close relation to the later occurrence of microencephaly following ENU-administration, and that ENU affects mainly S-phase cells and causes apoptosis.
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teratologic studies on rat perinates and offspring from dams treated with ethylnitrosourea ENU
Experimental Animals, 2000Co-Authors: Keiichi Katayama, Noriaki Ishigami, Michio Suzuki, Ryoichi Ohtsuka, Wijit Kiatipattanasakul, Hiroyuki NakayamaAbstract:Ethylnitrosourea (ENU), a well known DNA alkylating agent, induces anomalies in the central nervous system (CNS), craniofacial tissues, limbs and male reproductive organs. Recently we clarified that excess cell death caused by apoptosis occurred in these organs and tissues of rat fetuses from dams treated with ENU at day 13 of gestation (GD13). In this study, we examined fetuses at GD21 and offspring at 10 weeks of age after ENU administration to pregnant rats at GD13 in order to clarify the relationship between ENU-induced apoptosis in the fetal tissues and teratogenicity of ENU. Severe intrauterine growth retardation was observed in the ENU group, and the body weight of the offspring in the ENU group was significantly lower than that of the control group throughout the experiment. In addition, a high incidence of microencephaly, ectrodactyly and curved caudal vertebrae was observed in the offspring from dams treated with ENU at GD13. Judging from the results of our previous and present studies, it was strongly suggested that ENU-induced apoptosis in rat fetal tissues may play an important role in the induction of anomalies in the corresponding tissues.
Clemens Dasenbrock - One of the best experts on this subject based on the ideXlab platform.
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Tumor promotion by long-term UMTS electromagnetic field exposure in B6C3F1 mice prenatally treated with ENU
Reproductive Toxicology, 2008Co-Authors: T. Tillmann, Heinrich Ernst, Tina Reinhardt, Andreas K. Bitz, Joachim Streckert, Volkert Hansen, Ulrich Mohr, Clemens DasenbrockAbstract:Objective: To evaluate possible influences on tumor development in freely moving mice following exposure to a generic UMTS (universal mobile telecommunications system) test signal for 20 h/day on 7 days/week, starting as fetal exposure. Methods: The experiment was carried out as a one-generation study with prenatal exposure, using two EMF treatment groups ["UMTS high-dose group" + "UMTS mid-dose group" with additional ethylnitrosourea (ENU) treatment], and a sham-exposed control group in the EMF exposure device, in addition to an cage control group and a positive (ENU-treated) control group. Starting on day 6 of pregnancy maternal mice were UMTS-exposed, while lifetime exposure (up to 24 months) of the F1 descendants started on the day of birth. Maternal ethylnitrosourea administration (40mgENU/kg b.w.) was carried out on day 14 of pregnancy. The exposure was performed in a three-level exposure unit [sham, medium-dose (4.8W/m2), high-dose (48W/m2)] consisting of three stacked radial waveguides (one level for each dose group) and housing up to 60 female B6C3F1 mice (3 per cage) per level. Histopathological examinationwas limited to neoplasms and pre-neoplastic lesions of the brain, lungs, liver, spleen, kidneys, mesenterial lymph nodes, and gross lesions. Results/conclusion: The cage control group,shamexposure group and UMTS high-dose group revealed comparable tumor incidences in the target organs. The UMTS high-dose group, in contrast, showed a significantly increased number of pre-neoplastic liver foci as compared to the sham control and cage control groups. Analysis of the neoplastic and pre-neoplastic findings in the two ENU groups revealed some remarkable findings: A comparison of neoplastic lesions revealed an increased liver tumor rate and a significantly increased lung tumor incidence in the ENU/UMTS group as compared to the ENU control group. Incidences of hepatocellular adenoma(s) and bronchiolo-alveolar carcinoma(s) were significantly increased in the ENU groups after lifetime UMTS exposure. A Present address: Erwin L. Hahn Institute for Magnetic Resonance Imaging, Essen, Germany. With respect to bronchiolo-alveolar carcinoma(s) and hepatocellular adenoma(s), tumor multiplicity was significantly increased in the ENU/UMTS group as compared to the ENU control group. The incidence of metastasizing lung carcinoma(s) in the two ENU groups was doubled by the long-term UMTS exposure of the mice. In addition, the incidence of pre-neoplastic hepatocellular foci also increased significantly in the ENU/UMTS group as compared to the ENU control group. In conclusion, the study revealed distinct tumor-promoting effects of chronic UMTS exposure in this ENU mouse model. It currently remains unclear, however, to what extent these limited results (promotion of ENU-induced tumorigenesis by long-termUMTSexposure) are predictive of human carcinogenesis. Support by Compagnia di San Paolo, Torino, Italy, is gratefully acknowledged
Callista Yee - One of the best experts on this subject based on the ideXlab platform.
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ENU 3 functions in an unc 6 netrin dependent pathway parallel to unc 40 dcc frazzled for outgrowth and guidance of the touch receptor neurons in c elegans
Developmental Dynamics, 2014Co-Authors: Callista Yee, Roxana Oriana Florica, Jeffrey Fillingham, Marie T. KilleenAbstract:Background: UNC-6 and SLT-1 guide the migrations of the ventrally directed processes of the AVM and PVM touch receptor neurons and UNC-6 guides the axons of the DA and DB classes of motor neurons in C. elegans. The UNC-6 receptors are UNC-5 and UNC-40. The axon outgrowth defects of a subset of the DB motor neurons in the absence of UNC-5 are enhanced by mutations in ENU-3. Results: An ENU-3 mutation enhances defects in ventral guidance of the processes of the AVM and PVM touch receptor neurons, the dorsal guidance of the distal tip cell and causes additional architectural defects in axons in unc-40 mutant strains in an UNC-6 dependent manner. These observations suggest that ENU-3 and UNC-40 function in parallel pathways dependent on UNC-6. ENU-3 depends on the presence of UNC-40 for its full effect on motor neuron axon outgrowth. Conclusions: ENU-3 works in an UNC-6 dependent pathway parallel to UNC-40 in ventral guidance of AVM and PVM and in dorsal guidance of the distal tip cells. Motor neuron axon outgrowth defects are caused by the presence of UNC-40 and the absence of functional UNC-5 or UNC-6 and defects are enhanced by the absence of functional ENU-3. Developmental Dynamics 243:459–467, 2014. © 2013 Wiley Periodicals, Inc.
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ENU-3 is a novel motor axon outgrowth and guidance protein in C. elegans.
Developmental Biology, 2011Co-Authors: Callista Yee, Stephanie S. Sybingco, Viktoria Serdetchania, Ganna Kholkina, Matthew Bueno De Mesquita, Zafaryab Naqvi, Sang-hyeon Park, Karmen Lam, Marie T. KilleenAbstract:During the development of the nervous system, the migration of many cells and axons is guided by extracellular molecules. These molecules bind to receptors at the tips of the growth cones of migrating axons and trigger intracellular signaling to steer the axons along the correct trajectories. We have identified a novel mutant, ENU-3 (enhancer of Unc), that enhances the motor neuron axon outgrowth defects observed in strains of Caenorhabditis elegans that lack either the UNC-5 receptor or its ligand UNC-6/Netrin. Specifically, the double-mutant strains have enhanced axonal outgrowth defects mainly in DB4, DB5 and DB6 motor neurons. ENU-3 single mutants have weak motor neuron axon migration defects. Both outgrowth defects of double mutants and axon migration defects of ENU-3 mutants were rescued by expression of the H04D03.1 gene product. ENU-3/H04D03.1 encodes a novel predicted putative trans-membrane protein of 204 amino acids. It is a member of a family of highly homologous proteins of previously unknown function in the C. elegans genome. ENU-3 is expressed in the PVT interneuron and is weakly expressed in many cell bodies along the ventral cord, including those of the DA and DB motor neurons. We conclude that ENU-3 is a novel C. elegans protein that affects both motor axon outgrowth and guidance.