{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:02:42Z","timestamp":1791118962151,"version":"4.1.0"},"reference-count":24,"publisher":"Portland Press Ltd.","issue":"2","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2006,4,15]]},"abstract":"<jats:p>The TLX2 (HOX11L1, Ncx, Enx) and PHOX2B genes encode transcription factors crucial in the development of neural-crest-derived cells, leading to ANS (autonomic nervous system) specific neuronal lineages. Moreover, they share a similar expression pattern and are both involved in downstream steps of BMP (bone morphogenetic protein) signalling. In an attempt to reconstruct the gene network sustaining the correct development of the ANS, we have undertaken an in vitro experimental strategy to identify direct upstream regulators of the TLX2 gene. After characterizing a sequence displaying enhancer property in its 5\u2032 flanking region, we confirmed the functional link between the human PHOX2B and TLX2 genes. Transient transfections and electrophoretic-mobility-shift assays suggested that PHOX2B is able to bind the cell-specific element in the 5\u2032 regulatory region of the TLX2 gene, determining its transactivation in neuroblastoma cells. Such interaction was also confirmed in vivo by means of chromatin immunoprecipitation assay and, in addition, up-regulation of endogenous TLX2 mRNA level was demonstrated following PHOX2B over-expression, by quantitative real-time PCR. Finally, PHOX2B proteins carrying mutations responsible for CCHS (congenital central hypoventilation syndrome) development showed a severe impairment in activating TLX2 expression, both in vitro and in vivo. Taken together, these results support the PHOX2B\u2013TLX2 promoter interaction, suggesting a physiological role in the transcription-factor cascade underlying the differentiation of neuronal lineages of the ANS during human embryogenesis.<\/jats:p>","DOI":"10.1042\/bj20051386","type":"journal-article","created":{"date-parts":[[2006,3,28]],"date-time":"2006-03-28T12:39:20Z","timestamp":1143549560000},"page":"355-361","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["The <i>TLX2<\/i> homeobox gene is a transcriptional target of PHOX2B in neural-crest-derived cells"],"prefix":"10.1042","volume":"395","author":[{"given":"Silvia","family":"Borghini","sequence":"first","affiliation":[{"name":"Laboratorio di Genetica Molecolare, Istituto Gerolamo Gaslini, 16148 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Bachetti","sequence":"additional","affiliation":[{"name":"Laboratorio di Genetica Molecolare, Istituto Gerolamo Gaslini, 16148 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Fava","sequence":"additional","affiliation":[{"name":"Laboratorio di Genetica Molecolare, Istituto Gerolamo Gaslini, 16148 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Di\u00a0Duca","sequence":"additional","affiliation":[{"name":"Laboratorio di Fisiopatologia dell'Uremia, Istituto Giannina Gaslini, 16148 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Cargnin","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacologia, Facolta' di Medicina, Universita' di Milano e CNR Istituto di Neuroscienze, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Fornasari","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacologia, Facolta' di Medicina, Universita' di Milano e CNR Istituto di Neuroscienze, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Ravazzolo","sequence":"additional","affiliation":[{"name":"Laboratorio di Genetica Molecolare, Istituto Gerolamo Gaslini, 16148 Genova, Italy"},{"name":"Dipartimento di Pediatria e CEBR, Universit\u00e0 di Genova, Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Ceccherini","sequence":"additional","affiliation":[{"name":"Laboratorio di Genetica Molecolare, Istituto Gerolamo Gaslini, 16148 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2006,3,28]]},"reference":[{"key":"2021112214082141500_B1","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s004290050061","article-title":"Ncx, a Hox11 related gene, is expressed in a variety of tissues derived from neural crest cells","volume":"195","author":"Hatano","year":"1997","journal-title":"Anat. 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