{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T15:54:59Z","timestamp":1783353299963,"version":"3.54.6"},"reference-count":65,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2017,1,1]],"date-time":"2017-01-01T00:00:00Z","timestamp":1483228800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/100001260","name":"National Organization for Rare Disorders","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001260","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Lmx1b is a homeodomain transcription factor responsible for limb dorsalization. Despite striking double-ventral (loss-of-function) and double-dorsal (gain-of-function) limb phenotypes, no direct gene targets in the limb have been confirmed. To determine direct targets, we performed a chromatin immunoprecipitation against Lmx1b at E12.5 followed by next generation sequencing (ChIP-seq). Nearly 84% (n=617) of the Lmx1b-bound genomic intervals (LBIs) identified overlap with chromatin regulatory marks indicative of potential cis-regulatory modules (PCRMs). In addition, 73 LBIs mapped to known CRMs active during limb development. We compared Lmx1b-bound PCRMs to genes differentially expressed by Lmx1b and found 292 PCRMs within 1 Mb of 254 Lmx1b-regulated genes. Gene ontologic analysis suggests that Lmx1b targets extracellular matrix production, bone\/joint formation, axonal guidance, vascular development, cell proliferation and cell movement. We validated the functional activity of a PCRM associated with joint-related Gdf5 that provides a mechanism for Lmx1b-mediated joint modification and a PCRM associated with Lmx1b that suggests a role in autoregulation. This is the first report to describe genome-wide Lmx1b binding during limb development, directly linking Lmx1b to targets that accomplish limb dorsalization.<\/jats:p>","DOI":"10.1242\/dev.146332","type":"journal-article","created":{"date-parts":[[2017,4,28]],"date-time":"2017-04-28T20:40:20Z","timestamp":1493412020000},"source":"Crossref","is-referenced-by-count":24,"title":["Lmx1b-targeted\n                    <i>cis<\/i>\n                    -regulatory modules involved in limb dorsalization"],"prefix":"10.1242","author":[{"given":"Endika","family":"Haro","sequence":"first","affiliation":[{"name":"Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Billy A.","family":"Watson","sequence":"additional","affiliation":[{"name":"Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M.","family":"Feenstra","sequence":"additional","affiliation":[{"name":"Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Tegeler","sequence":"additional","affiliation":[{"name":"Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charmaine U.","family":"Pira","sequence":"additional","affiliation":[{"name":"Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subburaman","family":"Mohan","sequence":"additional","affiliation":[{"name":"Musculoskeletal Disease Center, Loma Linda VA HealthCare System, Loma Linda, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1241-4273","authenticated-orcid":false,"given":"Kerby C.","family":"Oberg","sequence":"additional","affiliation":[{"name":"Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2017,1,1]]},"reference":[{"key":"2021042608515681500_DEV146332C1","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1101\/gr.213066.116","article-title":"Characterization of hundreds of regulatory landscapes in developing limbs reveals two regimes of chromatin folding","volume":"27","author":"Andrey","year":"2017","journal-title":"Genome Res."},{"key":"2021042608515681500_DEV146332C2","doi-asserted-by":"publisher","first-page":"3713","DOI":"10.1242\/dev.02873","article-title":"Cell tracing reveals a dorsoventral lineage restriction plane in the mouse limb bud mesenchyme","volume":"134","author":"Arques","year":"2007","journal-title":"Development"},{"key":"2021042608515681500_DEV146332C3","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1006\/mcne.2002.1182","article-title":"CNS expression pattern of Lmx1b and coexpression with ptx genes suggest functional cooperativity in the development of forebrain motor control systems","volume":"21","author":"Asbreuk","year":"2002","journal-title":"Mol Cell Neurosci."},{"key":"2021042608515681500_DEV146332C4","doi-asserted-by":"publisher","first-page":"W39","DOI":"10.1093\/nar\/gkv416","article-title":"The MEME suite","volume":"43","author":"Bailey","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2021042608515681500_DEV146332C5","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/S0925-4773(98)00065-3","article-title":"The loss of ventral ectoderm identity correlates with the inability to form an AER in the legless hindlimb bud","volume":"74","author":"Bell","year":"1998","journal-title":"Mech. 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