{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T23:58:59Z","timestamp":1791417539671,"version":"4.3.3"},"reference-count":40,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5400","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[1999,1,15]]},"abstract":"<jats:p>\n            The function of the central cannabinoid receptor (CB\n            <jats:sub>1<\/jats:sub>\n            ) was investigated by invalidating its gene. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive role of the CB\n            <jats:sub>1<\/jats:sub>\n            receptor in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced. These observations suggest that the CB\n            <jats:sub>1<\/jats:sub>\n            receptor is involved in the motivational properties of opiates and in the development of physical dependence and extend the concept of an interconnected role of CB\n            <jats:sub>1<\/jats:sub>\n            and opiate receptors in the brain areas mediating addictive behavior.\n          <\/jats:p>","DOI":"10.1126\/science.283.5400.401","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T09:37:20Z","timestamp":1027762640000},"page":"401-404","source":"Crossref","is-referenced-by-count":3446,"title":["Unresponsiveness to Cannabinoids and Reduced Addictive Effects of Opiates in CB\n            <sub>1<\/sub>\n            Receptor Knockout Mice"],"prefix":"10.1126","volume":"283","author":[{"given":"Catherine","family":"Ledent","sequence":"first","affiliation":[{"name":"C. Ledent and M. Parmentier, IRIBHN, Universite\u0301 libre de Bruxelles, B-1070 Brussels, Belgium. O. Valverde, F. Beslot, B. P. Roques, De\u0301partement de Pharmacochimie Mole\u0301culaire et Structurale, INSERM U266, URA D1500 CNRS, Universite\u0301 Rene\u0301Descartes, 75270 Paris Cedex, France. G. Cossu and W. Fratta, \u201cBernard B. Brodie\u201d Department of Neuroscience, University of Cagliari, 09124, Cagliari, Italy. F. Petitet, G. A. Bo\u0308hme, A. Imperato, Rho\u0302ne-Poulenc-Rorer S.A., Centre de Recherche de Vitry-Alfortville,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Valverde","sequence":"additional","affiliation":[{"name":"C. Ledent and M. Parmentier, IRIBHN, Universite\u0301 libre de Bruxelles, B-1070 Brussels, Belgium. O. Valverde, F. Beslot, B. P. Roques, De\u0301partement de Pharmacochimie Mole\u0301culaire et Structurale, INSERM U266, URA D1500 CNRS, Universite\u0301 Rene\u0301Descartes, 75270 Paris Cedex, France. G. Cossu and W. Fratta, \u201cBernard B. Brodie\u201d Department of Neuroscience, University of Cagliari, 09124, Cagliari, Italy. F. Petitet, G. A. Bo\u0308hme, A. Imperato, Rho\u0302ne-Poulenc-Rorer S.A., Centre de Recherche de Vitry-Alfortville,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregorio","family":"Cossu","sequence":"additional","affiliation":[{"name":"C. Ledent and M. Parmentier, IRIBHN, Universite\u0301 libre de Bruxelles, B-1070 Brussels, Belgium. O. Valverde, F. Beslot, B. P. Roques, De\u0301partement de Pharmacochimie Mole\u0301culaire et Structurale, INSERM U266, URA D1500 CNRS, Universite\u0301 Rene\u0301Descartes, 75270 Paris Cedex, France. G. Cossu and W. Fratta, \u201cBernard B. Brodie\u201d Department of Neuroscience, University of Cagliari, 09124, Cagliari, Italy. F. Petitet, G. A. Bo\u0308hme, A. Imperato, Rho\u0302ne-Poulenc-Rorer S.A., Centre de Recherche de Vitry-Alfortville,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franc\u0327ois","family":"Petitet","sequence":"additional","affiliation":[{"name":"C. Ledent and M. Parmentier, IRIBHN, Universite\u0301 libre de Bruxelles, B-1070 Brussels, Belgium. O. Valverde, F. Beslot, B. P. Roques, De\u0301partement de Pharmacochimie Mole\u0301culaire et Structurale, INSERM U266, URA D1500 CNRS, Universite\u0301 Rene\u0301Descartes, 75270 Paris Cedex, France. G. Cossu and W. Fratta, \u201cBernard B. Brodie\u201d Department of Neuroscience, University of Cagliari, 09124, Cagliari, Italy. F. Petitet, G. A. Bo\u0308hme, A. Imperato, Rho\u0302ne-Poulenc-Rorer S.A., Centre de Recherche de Vitry-Alfortville,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Franc\u0327ois","family":"Aubert","sequence":"additional","affiliation":[{"name":"C. Ledent and M. Parmentier, IRIBHN, Universite\u0301 libre de Bruxelles, B-1070 Brussels, Belgium. O. Valverde, F. Beslot, B. P. Roques, De\u0301partement de Pharmacochimie Mole\u0301culaire et Structurale, INSERM U266, URA D1500 CNRS, Universite\u0301 Rene\u0301Descartes, 75270 Paris Cedex, France. G. Cossu and W. Fratta, \u201cBernard B. Brodie\u201d Department of Neuroscience, University of Cagliari, 09124, Cagliari, Italy. F. Petitet, G. A. Bo\u0308hme, A. Imperato, Rho\u0302ne-Poulenc-Rorer S.A., Centre de Recherche de Vitry-Alfortville,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franc\u0327oise","family":"Beslot","sequence":"additional","affiliation":[{"name":"C. Ledent and M. Parmentier, IRIBHN, Universite\u0301 libre de Bruxelles, B-1070 Brussels, Belgium. O. Valverde, F. Beslot, B. P. Roques, De\u0301partement de Pharmacochimie Mole\u0301culaire et Structurale, INSERM U266, URA D1500 CNRS, Universite\u0301 Rene\u0301Descartes, 75270 Paris Cedex, France. G. Cossu and W. Fratta, \u201cBernard B. Brodie\u201d Department of Neuroscience, University of Cagliari, 09124, Cagliari, Italy. F. Petitet, G. A. Bo\u0308hme, A. Imperato, Rho\u0302ne-Poulenc-Rorer S.A., Centre de Recherche de Vitry-Alfortville,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg A.","family":"Bo\u0308hme","sequence":"additional","affiliation":[{"name":"C. Ledent and M. Parmentier, IRIBHN, Universite\u0301 libre de Bruxelles, B-1070 Brussels, Belgium. O. Valverde, F. Beslot, B. P. Roques, De\u0301partement de Pharmacochimie Mole\u0301culaire et Structurale, INSERM U266, URA D1500 CNRS, Universite\u0301 Rene\u0301Descartes, 75270 Paris Cedex, France. G. Cossu and W. Fratta, \u201cBernard B. Brodie\u201d Department of Neuroscience, University of Cagliari, 09124, Cagliari, Italy. F. Petitet, G. A. Bo\u0308hme, A. Imperato, Rho\u0302ne-Poulenc-Rorer S.A., Centre de Recherche de Vitry-Alfortville,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Assunta","family":"Imperato","sequence":"additional","affiliation":[{"name":"C. Ledent and M. Parmentier, IRIBHN, Universite\u0301 libre de Bruxelles, B-1070 Brussels, Belgium. O. Valverde, F. Beslot, B. P. Roques, De\u0301partement de Pharmacochimie Mole\u0301culaire et Structurale, INSERM U266, URA D1500 CNRS, Universite\u0301 Rene\u0301Descartes, 75270 Paris Cedex, France. G. Cossu and W. Fratta, \u201cBernard B. Brodie\u201d Department of Neuroscience, University of Cagliari, 09124, Cagliari, Italy. F. Petitet, G. A. Bo\u0308hme, A. Imperato, Rho\u0302ne-Poulenc-Rorer S.A., Centre de Recherche de Vitry-Alfortville,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Pedrazzini","sequence":"additional","affiliation":[{"name":"C. Ledent and M. Parmentier, IRIBHN, Universite\u0301 libre de Bruxelles, B-1070 Brussels, Belgium. O. Valverde, F. Beslot, B. P. Roques, De\u0301partement de Pharmacochimie Mole\u0301culaire et Structurale, INSERM U266, URA D1500 CNRS, Universite\u0301 Rene\u0301Descartes, 75270 Paris Cedex, France. G. Cossu and W. Fratta, \u201cBernard B. Brodie\u201d Department of Neuroscience, University of Cagliari, 09124, Cagliari, Italy. F. Petitet, G. A. Bo\u0308hme, A. Imperato, Rho\u0302ne-Poulenc-Rorer S.A., Centre de Recherche de Vitry-Alfortville,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard P.","family":"Roques","sequence":"additional","affiliation":[{"name":"C. Ledent and M. Parmentier, IRIBHN, Universite\u0301 libre de Bruxelles, B-1070 Brussels, Belgium. O. Valverde, F. Beslot, B. P. Roques, De\u0301partement de Pharmacochimie Mole\u0301culaire et Structurale, INSERM U266, URA D1500 CNRS, Universite\u0301 Rene\u0301Descartes, 75270 Paris Cedex, France. G. Cossu and W. Fratta, \u201cBernard B. Brodie\u201d Department of Neuroscience, University of Cagliari, 09124, Cagliari, Italy. F. Petitet, G. A. Bo\u0308hme, A. Imperato, Rho\u0302ne-Poulenc-Rorer S.A., Centre de Recherche de Vitry-Alfortville,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilbert","family":"Vassart","sequence":"additional","affiliation":[{"name":"C. Ledent and M. Parmentier, IRIBHN, Universite\u0301 libre de Bruxelles, B-1070 Brussels, Belgium. O. Valverde, F. Beslot, B. P. Roques, De\u0301partement de Pharmacochimie Mole\u0301culaire et Structurale, INSERM U266, URA D1500 CNRS, Universite\u0301 Rene\u0301Descartes, 75270 Paris Cedex, France. G. Cossu and W. Fratta, \u201cBernard B. Brodie\u201d Department of Neuroscience, University of Cagliari, 09124, Cagliari, Italy. F. Petitet, G. A. Bo\u0308hme, A. Imperato, Rho\u0302ne-Poulenc-Rorer S.A., Centre de Recherche de Vitry-Alfortville,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Fratta","sequence":"additional","affiliation":[{"name":"C. Ledent and M. Parmentier, IRIBHN, Universite\u0301 libre de Bruxelles, B-1070 Brussels, Belgium. O. Valverde, F. Beslot, B. P. Roques, De\u0301partement de Pharmacochimie Mole\u0301culaire et Structurale, INSERM U266, URA D1500 CNRS, Universite\u0301 Rene\u0301Descartes, 75270 Paris Cedex, France. G. Cossu and W. Fratta, \u201cBernard B. Brodie\u201d Department of Neuroscience, University of Cagliari, 09124, Cagliari, Italy. F. Petitet, G. A. Bo\u0308hme, A. Imperato, Rho\u0302ne-Poulenc-Rorer S.A., Centre de Recherche de Vitry-Alfortville,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Parmentier","sequence":"additional","affiliation":[{"name":"C. Ledent and M. Parmentier, IRIBHN, Universite\u0301 libre de Bruxelles, B-1070 Brussels, Belgium. O. Valverde, F. Beslot, B. P. Roques, De\u0301partement de Pharmacochimie Mole\u0301culaire et Structurale, INSERM U266, URA D1500 CNRS, Universite\u0301 Rene\u0301Descartes, 75270 Paris Cedex, France. G. Cossu and W. Fratta, \u201cBernard B. Brodie\u201d Department of Neuroscience, University of Cagliari, 09124, Cagliari, Italy. F. Petitet, G. A. Bo\u0308hme, A. Imperato, Rho\u0302ne-Poulenc-Rorer S.A., Centre de Recherche de Vitry-Alfortville,..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1146\/annurev.pharmtox.38.1.179","volume":"38","author":"Felder C. C.","year":"1998","unstructured":"Felder C. C., Glass M., Annu. Rev. Pharmacol. Toxicol. 38, 179 (1998);","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"e_1_3_1_2_3","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0074-7742(08)60667-4","volume":"39","author":"Abood M. E.","year":"1996","unstructured":"Abood M. E., Martin B. R., Int. Rev. Neurobiol. 39, 197 (1996).","journal-title":"Int. Rev. Neurobiol."},{"key":"e_1_3_1_3_2","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/346561a0","volume":"346","author":"Matsuda L. A.","year":"1990","unstructured":"Matsuda L. A., Lolait S. J., Brownstein M. J., Young A. C., Bonner T. I., Nature 346, 561 (1990);","journal-title":"Nature"},{"key":"e_1_3_1_3_3","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1042\/bj2790129","volume":"279","author":"G\u00e9rard C.","year":"1991","unstructured":"G\u00e9rard C., Mollereau C., Vassart G., Parmentier M., Biochem. J. 279, 129 (1991);","journal-title":"Biochem. J."},{"key":"e_1_3_1_3_4","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/365061a0","volume":"365","author":"Munro S.","year":"1993","unstructured":"Munro S., Thomas K. L., Abu-Shaar M., Nature 365, 61 (1993).","journal-title":"Nature"},{"key":"e_1_3_1_4_2","unstructured":"The CB 1 gene was cloned from a 129\/Sv mouse genomic library and the single coding exon was mapped and sequenced (EMBL\/GenBank ). A PGK-Neo cassette was inserted between Avr II and Sfi I sites located 1073 base pairs apart replacing the first 233 codons of the gene. Homologous recombination in R1 cells and aggregation with CD1 eight\u2013cell stage embryos were performed as described ["},{"key":"e_1_3_1_4_3","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/41771","volume":"388","author":"Ledent C.","year":"1997","unstructured":"Ledent C., et al., Nature 388, 674 (1997);","journal-title":"Nature"},{"key":"e_1_3_1_4_4","unstructured":"]. A recombinant line was used to generate chimeras allowing germ line transmission of the mutant gene. Heterozygous mice were bred for five generations on a CD1 background before generating the CB 1 +\/+ and CB 1 \u2212\/\u2212 mice used in this study."},{"key":"e_1_3_1_5_2","unstructured":"[ 3 H]WIN55 212-2 and [ 3 H]SR141 716A binding assays were performed as described [J. E. Kuster J. I. Stevenson S. J. Ward T. E. D'Ambra"},{"key":"e_1_3_1_5_3","first-page":"1352","volume":"264","author":"Haycock D. A.","year":"1993","unstructured":"Haycock D. A., J. Pharmacol. Exp. Ther. 264, 1352 (1993);","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_3_1_5_4","unstructured":"]. Using forebrain membranes from CB 1 +\/+ mice we found a dissociation constant ( K d ) of 0.73 \u00b1 0.12 nM and a maximum binding capacity ( B max ) of 1.17 \u00b1 0.16 pmol of [ 3 H]WIN55 212-2 per milligram of protein for [ 3 H]WIN55 212-2 and a K d of 0.74 \u00b1 0.11 nM and a B max of 1.07 \u00b1 0.04 pmol of [ 3 H]SR141 716A per milligram of protein for [ 3 H]SR141 716A. No binding was detected on forebrain or cerebellar membranes from CB 1 \u2212\/\u2212 mice."},{"key":"e_1_3_1_6_2","unstructured":"Animals were housed at 21\u00b0 \u00b1 1\u00b0C with free access to food and water. Experiments were conducted in accordance with local ethical guidelines. The measurement of locomotor activity and the open-field and elevated plus maze tests were performed as described (24). Mice were exposed to the open field for three consecutive days. The number of squares crossed was as follows: wild type: 170 \u00b1 12 127 \u00b1 10 and 91 \u00b1 11 for first second and third days respectively; knockout: 256 \u00b1 20 ( P < 0.01) 158 \u00b1 15 (NS) and 120 \u00b1 16 (NS) for first second and third days respectively ( t test n = 15 per group)."},{"key":"e_1_3_1_7_2","unstructured":"The spontaneous alternation test was conducted as described (24). The percentage of alternation was measured as the number of times the animal visited consecutively all three arms divided by the total number of visits during a 10-min period."},{"key":"e_1_3_1_8_2","unstructured":"Nociceptive thresholds were monitored by applying thermal (tail-immersion and hot-plate tests) mechanical (tail-pressure test) or chemical stimuli (writhing test) (24). For the tail-immersion test mice were maintained in a cylinder and their tail was immersed in water at 50\u00b0C; latency to tail withdrawal was recorded. In the hot-plate test mice were placed on a surface heated to 50\u00b0C and the latencies for licking their paws and jumping were recorded. For the tail-pressure test increasing pressure (tip diameter: 1 mm) was applied to the tails of the mice until a withdrawal response was elicited. In the writhing test mice received 0.1 ml per 10 g of body weight of a 0.6% acetic acid solution by the intraperitoneal route and contractions of abdominal musculature (writhes) were counted between 5 and 15 min after the injection."},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/28393"},{"key":"e_1_3_1_10_2","unstructured":"Self-administration of WIN55 212-2 and morphine was performed as described ["},{"key":"e_1_3_1_10_3","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/S0306-4522(98)00052-9","volume":"85","author":"Martellotta M. C.","year":"1998","unstructured":"Martellotta M. C., Cossu G., Fattore L., Gessa G. L., Fratta W., Neuroscience 85, 327 (1998)].","journal-title":"Neuroscience"},{"key":"e_1_3_1_11_2","unstructured":"For \u0394 9 -THC dependence and withdrawal mice were injected twice daily for 5 days with \u0394 9 -THC (20 mg\/kg intraperitoneally) or vehicle (ethanol\/chremophor EL\/distilled water 1:1:18). On day 6 they received the morning injection and 4 hours later the cannabinoid antagonist SR141 716A [10 mg\/kg subcutaneously (sc)]. \u0394 9 -THC withdrawal was evaluated for 35 min as reported ["},{"key":"e_1_3_1_11_3","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1038\/sj.bjp.0702228","volume":"125","author":"Hutcheson D. M.","year":"1998","unstructured":"Hutcheson D. M., et al., Br. J. Pharmacol. 125, 1567 (1998)].","journal-title":"Br. J. Pharmacol."},{"key":"e_1_3_1_12_2","first-page":"1030","volume":"281","author":"Lake K. D.","year":"1997","unstructured":"Lake K. D., Compton D. R., Varga K., Martin B. R., Kunos G., J. Pharmacol. Exp. Therap. 281, 1030 (1997).","journal-title":"J. Pharmacol. Exp. Therap."},{"key":"e_1_3_1_13_2","unstructured":"Blood pressure and heart rate were recorded in conscious animals 4 hours after surgical implantation of catheters ["},{"key":"e_1_3_1_13_3","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1038\/nm0698-722","volume":"4","author":"Pedrazzini T.","year":"1998","unstructured":"Pedrazzini T., et al., Nature Med. 4, 722 (1998);","journal-title":"Nature Med."},{"key":"e_1_3_1_13_4","unstructured":"]. Agonists (100 \u03bcl of a 30% ethanol solution) were injected through a catheter inserted into the jugular vein. Basal values were as follows: blood pressure 113 \u00b1 2.4 (CB 1 +\/+ ) and 123 \u00b1 4.1 (CB 1 \u2212\/\u2212 ) mmHg; P > 0.05; heart rate 522 \u00b1 43 (CB 1 +\/+ ) and 494 \u00b1 38 (CB 1 \u2212\/\u2212 ) beats per minute; P > 0.05 t test n = 9."},{"key":"e_1_3_1_14_2","first-page":"10","volume":"262","author":"Welch S. P.","year":"1992","unstructured":"Welch S. P., Stevens D. L., J. Pharmacol. Exp. Ther. 262, 10 (1992).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.276.5321.2048"},{"key":"e_1_3_1_16_2","unstructured":"C. Ledent et al. data not shown."},{"key":"e_1_3_1_17_2","unstructured":"Opiate tolerance was induced by daily sc injection of morphine (20 mg\/kg) for 5 days followed by a sc 6 mg\/kg injection of morphine."},{"key":"e_1_3_1_18_2","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/0091-3057(92)90363-K","volume":"413","author":"Kuzmin A.","year":"1992","unstructured":"Kuzmin A., Zvartau E., Gessa G. L., Martellotta M. C., Fratta W., Pharmacol. Biochem. Behav. 413, 497 (1992).","journal-title":"Pharmacol. Biochem. Behav."},{"key":"e_1_3_1_19_2","unstructured":"Opiate dependence was induced by repeated intraperitoneal injection of morphine (or saline in controls) at an interval of 12 hours over 6 days (20 mg\/kg on day 1 to 100 mg\/kg on days 5 and 6). Withdrawal was precipitated by injecting naloxone (1 mg\/kg sc) 2 hours after the last morphine administration and was evaluated as reported ["},{"key":"e_1_3_1_19_3","doi-asserted-by":"publisher","DOI":"10.1126\/science.273.5275.657"},{"key":"e_1_3_1_19_4","unstructured":"]. A global score was calculated for each animal ["},{"key":"e_1_3_1_19_5","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/0028-3908(92)90051-P","volume":"21","author":"Maldonado R.","year":"1992","unstructured":"Maldonado R., Negus S., Koob G. F., Neuropharmacology 21, 1231 (1992)].","journal-title":"Neuropharmacology"},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/383819a0"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.276.5321.2050"},{"key":"e_1_3_1_22_2","first-page":"633","volume":"32","author":"Christie M. J.","year":"1987","unstructured":"Christie M. J., Williams J. T., North R. A., Mol. Pharmacol. 32, 633 (1987);","journal-title":"Mol. Pharmacol."},{"key":"e_1_3_1_22_3","unstructured":"; E. L. Way in Opioids II A. Herz Ed. (Springer-Verlag Berlin 1993) pp. 573\u2013592."},{"key":"e_1_3_1_23_2","first-page":"1381","volume":"268","author":"Smith P. B.","year":"1994","unstructured":"Smith P. B., Welch S. P., Martin B. R., J. Pharmacol. Exp. Ther. 268, 1381 (1994).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_3_1_24_2","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1016\/0024-3205(82)90132-1","volume":"31","author":"Lahti R. A.","year":"1982","unstructured":"Lahti R. A., Von Voigtlander P. F., Barsuhn C., Life Sci. 31, 2257 (1982).","journal-title":"Life Sci."},{"key":"e_1_3_1_25_2","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1093\/emboj\/17.4.886","volume":"17","author":"Simonin F.","year":"1998","unstructured":"Simonin F., et al., EMBO J. 17, 886 (1998).","journal-title":"EMBO J."},{"key":"e_1_3_1_26_2","unstructured":"We thank A. Nagy for R1 embryonic stem cells C. Dewolf and M. J. Simons for technical assistance and D. Penninck for discussions. Supported by the Interuniversity Poles of Attraction (Belgian State Prime Minister's Office Federal Service for Science Technology and Culture) the Fonds de la Recherche Scientifique M\u00e9dicale the EU BIOMED II programme and the Fondation M\u00e9dicale Reine Elisabeth. The scientific responsibility is assumed by the authors. C.L. is Chercheur Qualifi\u00e9 of the Fonds National de la Recherche Scientifique."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.283.5400.401","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T03:31:21Z","timestamp":1705116681000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.283.5400.401"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1999,1,15]]},"references-count":40,"journal-issue":{"issue":"5400","published-print":{"date-parts":[[1999,1,15]]}},"alternative-id":["10.1126\/science.283.5400.401"],"URL":"https:\/\/doi.org\/10.1126\/science.283.5400.401","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[1999,1,15]]}}}