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We assessed the ability of these NRs to form heterodimers with other members of the human NRs representing all major subgroups. The TLX ligand-binding domain (LBD) did not appear to form homodimers or interact directly with any other NR tested. The PNR LBD was able to form homodimers, but also exhibited robust interactions with the LBDs of peroxisome proliferator-activated receptor-<jats:italic>\u03b3<\/jats:italic> (PPAR<jats:italic>\u03b3<\/jats:italic>)\/NR1C3 and thyroid hormone receptor b (TRb) TR<jats:italic>\u03b2<\/jats:italic>\/NR1A2. The binding of PNR to PPAR<jats:italic>\u03b3<\/jats:italic> was specific for this paralog, as no interaction was observed with the LBDs of PPAR<jats:italic>\u03b1<\/jats:italic>\/NR1C1 or PPAR<jats:italic>\u03b4<\/jats:italic>\/NR1C2. In support of these findings, PPAR<jats:italic>\u03b3<\/jats:italic> and PNR were found to be co-expressed in human retinal tissue extracts and could be co-immunoprecipitated as a native complex. Selected sequence variants in the PNR LBD associated with human retinopathies, or a mutation in the dimerization region of PPAR<jats:italic>\u03b3<\/jats:italic> LBD associated with familial partial lipodystrophy type 3, were found to disrupt PNR\/PPAR<jats:italic>\u03b3<\/jats:italic> complex formation. Wild-type PNR, but not a PNR309G mutant, was able to repress PPAR<jats:italic>\u03b3<\/jats:italic>-mediated transcription in reporter assays. In summary, our results reveal novel heterodimer interactions in the NR superfamily, suggesting previously unknown functional interactions of PNR with PPAR<jats:italic>\u03b3<\/jats:italic> and TR<jats:italic>\u03b2<\/jats:italic> that have potential importance in retinal development and disease.<\/jats:p>","DOI":"10.1038\/cddis.2017.98","type":"journal-article","created":{"date-parts":[[2017,3,16]],"date-time":"2017-03-16T13:44:39Z","timestamp":1489671879000},"page":"e2677-e2677","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Heterodimers of photoreceptor-specific nuclear receptor (PNR\/NR2E3) and peroxisome proliferator-activated receptor-\u03b3 (PPAR\u03b3) are disrupted by retinal disease-associated mutations"],"prefix":"10.1038","volume":"8","author":[{"given":"Joel","family":"Fulton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bismoy","family":"Mazumder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan B","family":"Whitchurch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cintia J","family":"Monteiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary M","family":"Collins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun M","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria P","family":"Clemente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Hernandez-Quiles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winfried M","family":"Amoaku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula M","family":"Moran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel P","family":"Mongan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny L","family":"Persson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simak","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M","family":"Heery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,3,16]]},"reference":[{"key":"BFcddis201798_CR1","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1016\/0092-8674(95)90199-X","volume":"83","author":"DJ Mangelsdorf","year":"1995","unstructured":"Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K et al. 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