{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T17:34:06Z","timestamp":1771868046543,"version":"3.50.1"},"reference-count":32,"publisher":"Proceedings of the National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2002,11,12]]},"abstract":"<jats:p>\n            Cerebellar development occurs mainly postnatally and implies cell proliferation and migration. Hepatocyte growth factor (HGF) and Met are involved in mediating these responses in other tissues and are coexpressed in the cerebellum. Here we show that Met is localized in granule cell precursors and that cultures of these cells respond to HGF with proliferation. To study the role of HGF and Met in the cerebellum\n            <jats:italic>in vivo<\/jats:italic>\n            , we produced a viable hypomorphic Met mutant by knocking in the\n            <jats:italic>met<\/jats:italic>\n            locus a point mutation to abrogate the receptor Grb2-binding site. A similar mutant was previously described as perinatal lethal. In this \u201cfirst-generation\u201d knock-in the recombinant locus retained the\n            <jats:italic>Neo<\/jats:italic>\n            cassette (\n            <jats:italic>\n              Met\n              <jats:sup>grb2\/grb2neo+<\/jats:sup>\n            <\/jats:italic>\n            ). In the knock-in presented here\n            <jats:italic>Neo<\/jats:italic>\n            was\n            <jats:italic>Loxed<\/jats:italic>\n            and excised by\n            <jats:italic>Cre<\/jats:italic>\n            recombinase, which led to higher tissue levels of Met\n            <jats:sup>grb2<\/jats:sup>\n            protein, sufficient to rescue viability. In\n            <jats:italic>\n              Met\n              <jats:sup>grb2\/grb2neo\u2212<\/jats:sup>\n            <\/jats:italic>\n            mice the size of the cerebellum was reduced and foliation defects were evident, especially in the central and posterior half of the\n            <jats:italic>vermis<\/jats:italic>\n            . Proliferation of granule precursors\n            <jats:italic>in vivo<\/jats:italic>\n            was 25% lower than in controls. In cultures of mutant granule cells HGF-induced microtubule-associated protein kinase activation was reduced and transient. Behavioral tests indicated a balance impairment in\n            <jats:italic>\n              Met\n              <jats:sup>grb2\/grb2neo\u2212<\/jats:sup>\n            <\/jats:italic>\n            mice. Altogether these data indicate that normal cerebellar development and, possibly, function, require HGF and Met, and that proliferation of granule cells in the cerebellum critically depends on full HGF\/Met signaling.\n          <\/jats:p>","DOI":"10.1073\/pnas.222362099","type":"journal-article","created":{"date-parts":[[2002,11,12]],"date-time":"2002-11-12T18:44:20Z","timestamp":1037126660000},"page":"15200-15205","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":73,"title":["Viable hypomorphic signaling mutant of the Met receptor reveals a role for hepatocyte growth factor in postnatal cerebellar development"],"prefix":"10.1073","volume":"99","author":[{"given":"Alessandro","family":"Ieraci","sequence":"first","affiliation":[{"name":"Department of Medical Sciences, Universit\u00e0 del Piemonte Orientale Amedeo Avogadro, Via Solaroli 17, 28100 Novara, Italy; and Department of Anatomy, Pharmacology and Forensic Medicine, Universit\u00e0 degli Studi di Torino, Corso Massimo D'Azeglio 52, 10126 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo E.","family":"Forni","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Universit\u00e0 del Piemonte Orientale Amedeo Avogadro, Via Solaroli 17, 28100 Novara, Italy; and Department of Anatomy, Pharmacology and Forensic Medicine, Universit\u00e0 degli Studi di Torino, Corso Massimo D'Azeglio 52, 10126 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carola","family":"Ponzetto","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Universit\u00e0 del Piemonte Orientale Amedeo Avogadro, Via Solaroli 17, 28100 Novara, Italy; and Department of Anatomy, Pharmacology and Forensic Medicine, Universit\u00e0 degli Studi di Torino, Corso Massimo D'Azeglio 52, 10126 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"341","published-online":{"date-parts":[[2002,10,23]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80682-0"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(99)80195-X"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.126.14.3089"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/5669"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80938-1"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(96)00046-9"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9861(19961223)376:4<653::AID-CNE11>3.0.CO;2-N"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-3806(97)00015-1"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4547(20000215)59:4<489::AID-JNR3>3.0.CO;2-9"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/373699a0"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/376768a0"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81372-0"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/6310"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/0169-328X(95)00075-4"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.24.14119"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1200879"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.22.13116"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/23.24.5080"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.4.1488"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(01)00261-1"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90318-2"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.1052"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/gene.10024"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(95)00578-W"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a021283"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1006\/mcne.1999.0803"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.11.24.3341"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/11896"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/0165-3806(96)00492-0"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)00264-1"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.24.14118"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203859"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.222362099","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T11:49:39Z","timestamp":1649850579000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.222362099"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,10,23]]},"references-count":32,"journal-issue":{"issue":"23","published-print":{"date-parts":[[2002,11,12]]}},"alternative-id":["10.1073\/pnas.222362099"],"URL":"https:\/\/doi.org\/10.1073\/pnas.222362099","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,10,23]]},"assertion":[{"value":"2002-06-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2002-10-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}