{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T04:05:33Z","timestamp":1792037133944,"version":"4.4.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"3-4","license":[{"start":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T00:00:00Z","timestamp":1612137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["2R01DK065655"],"award-info":[{"award-number":["2R01DK065655"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1U54DK126087"],"award-info":[{"award-number":["1U54DK126087"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["3P30DK074038"],"award-info":[{"award-number":["3P30DK074038"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["F31HL150898"],"award-info":[{"award-number":["F31HL150898"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5T32HL007918-20"],"award-info":[{"award-number":["5T32HL007918-20"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DK114008"],"award-info":[{"award-number":["R01DK114008"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Primary cilia are critical sensory and signaling compartments present on most mammalian cell types. These specialized structures require a unique signaling protein composition relative to the rest of the cell to carry out their functions. Defects in ciliary structure and signaling result in a broad group of disorders collectively known as ciliopathies. One ciliopathy, Bardet\u2013Biedl syndrome (BBS; OMIM 209900), presents with diverse clinical features, many of which are attributed to defects in ciliary signaling during both embryonic development and postnatal life. For example, patients exhibit obesity, polydactyly, hypogonadism, developmental delay and skeletal abnormalities along with sensory and cognitive deficits, but for many of these phenotypes it is uncertain, which are developmental in origin. A subset of BBS proteins assembles into the core BBSome complex, which is responsible for mediating transport of membrane proteins into and out of the cilium, establishing it as a sensory and signaling hub. Here, we describe two new mouse models for BBS resulting from a targeted LacZ gene trap allele (Bbs5\u2212\/\u2212) that is a predicted congenital null mutation and conditional (Bbs5flox\/flox) allele of Bbs5. Bbs5\u2212\/\u2212 mice develop a complex phenotype consisting of increased pre-weaning lethality craniofacial and skeletal defects, ventriculomegaly, infertility and pituitary anomalies. Utilizing the conditional allele, we show that the male fertility defects, ventriculomegaly and pituitary abnormalities are only present when Bbs5 is disrupted prior to postnatal day 7, indicating a developmental origin. In contrast, mutation of Bbs5 results in obesity, independent of the age of Bbs5 loss.<\/jats:p>","DOI":"10.1093\/hmg\/ddab039","type":"journal-article","created":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T22:19:49Z","timestamp":1612304389000},"page":"234-246","source":"Crossref","is-referenced-by-count":20,"title":["A mouse model of BBS identifies developmental and homeostatic effects of BBS5 mutation and identifies novel pituitary abnormalities"],"prefix":"10.1093","volume":"30","author":[{"given":"Melissa R","family":"Bentley-Ford","sequence":"first","affiliation":[{"name":"Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Staci E","family":"Engle","sequence":"additional","affiliation":[{"name":"Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey R","family":"Clearman","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney J","family":"Haycraft","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reagan S","family":"Andersen","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy J","family":"Croyle","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Addison B","family":"Rains","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas F","family":"Berbari","sequence":"additional","affiliation":[{"name":"Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley K","family":"Yoder","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,2,9]]},"reference":[{"key":"2021081104103527400_ref1","doi-asserted-by":"crossref","first-page":"R421","DOI":"10.1016\/j.cub.2018.03.010","article-title":"How the ciliary membrane is organized inside-out to communicate outside-in","volume":"28","author":"Garcia","year":"2018","journal-title":"Curr. Biol."},{"key":"2021081104103527400_ref2","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/j.cell.2007.03.053","article-title":"A core complex of BBS proteins cooperates with the GTPase Rab 8 to promote ciliary membrane biogenesis","volume":"129","author":"Nachury","year":"2007","journal-title":"Cell"},{"key":"2021081104103527400_ref3","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/j.devcel.2008.11.001","article-title":"A BBSome subunit links ciliogenesis, microtubule stability, and acetylation","volume":"15","author":"Loktev","year":"2008","journal-title":"Dev. Cell"},{"key":"2021081104103527400_ref4","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1073\/pnas.1901665117","article-title":"Intraflagellar transport protein RABL5\/IFT22 recruits the BBSome to the basal body through the GTPase ARL6\/BBS3","volume":"117","author":"Xue","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021081104103527400_ref5","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1016\/j.cell.2010.05.015","article-title":"The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia","volume":"141","author":"Jin","year":"2010","journal-title":"Cell"},{"key":"2021081104103527400_ref6","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1038\/nsmb.2920","article-title":"Structural basis for membrane targeting of the BBSome by ARL6","volume":"21","author":"Mourao","year":"2014","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2021081104103527400_ref7","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1002358","article-title":"A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and smoothened","volume":"7","author":"Seo","year":"2011","journal-title":"PLoS Genet."},{"key":"2021081104103527400_ref8","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.55954","article-title":"Near-atomic structures of the BBSome reveal the basis for BBSome activation and binding to GPCR cargoes","volume":"9","author":"Yang","year":"2020","journal-title":"elife"},{"key":"2021081104103527400_ref9","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s13052-019-0659-1","article-title":"Mutation profile of BBS genes in patients with Bardet-Biedl syndrome: an Italian study","volume":"45","author":"Manara","year":"2019","journal-title":"Ital. J. Pediatr."},{"key":"2021081104103527400_ref10","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/S0092-8674(04)00450-7","article-title":"Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene","volume":"117","author":"Li","year":"2004","journal-title":"Cell"},{"key":"2021081104103527400_ref11","doi-asserted-by":"crossref","first-page":"F574","DOI":"10.1152\/ajprenal.00150.2010","article-title":"Inactivation of Bardet-Biedl syndrome genes causes kidney defects","volume":"300","author":"Guo","year":"2011","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"2021081104103527400_ref12","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1016\/j.ekir.2020.06.017","article-title":"Exploring key challenges of understanding the pathogenesis of kidney disease in Bardet-Biedl syndrome","volume":"5","author":"Marchese","year":"2020","journal-title":"Kidney Int. Rep."},{"key":"2021081104103527400_ref13","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1038\/ng1418","article-title":"Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse","volume":"36","author":"Kulaga","year":"2004","journal-title":"Nat. Genet."},{"key":"2021081104103527400_ref14","doi-asserted-by":"crossref","first-page":"19422","DOI":"10.1073\/pnas.0708571104","article-title":"A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity","volume":"104","author":"Davis","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021081104103527400_ref15","doi-asserted-by":"crossref","first-page":"16588","DOI":"10.1073\/pnas.0405496101","article-title":"Bbs 2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin","volume":"101","author":"Nishimura","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021081104103527400_ref16","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1093\/hmg\/dds004","article-title":"BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes","volume":"21","author":"Zhang","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"2021081104103527400_ref17","doi-asserted-by":"crossref","first-page":"10320","DOI":"10.1073\/pnas.1016531108","article-title":"Loss of Bardet-Biedl syndrome protein-8 (BBS8) perturbs olfactory function, protein localization, and axon targeting","volume":"108","author":"Tadenev","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021081104103527400_ref18","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1167\/iovs.18-25210","article-title":"Progressive characterization of visual phenotype in Bardet-Biedl syndrome mutant mice","volume":"60","author":"Kretschmer","year":"2019","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"2021081104103527400_ref19","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1167\/iovs.61.10.17","article-title":"BBSome component BBS5 is required for cone photoreceptor protein trafficking and outer segment maintenance","volume":"61","author":"Bales","year":"2020","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"2021081104103527400_ref20","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.cmet.2012.08.005","article-title":"BBS-induced ciliary defect enhances adipogenesis, causing paradoxical higher-insulin sensitivity, glucose usage, and decreased inflammatory response","volume":"16","author":"Marion","year":"2012","journal-title":"Cell Metab."},{"key":"2021081104103527400_ref21","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1005890","article-title":"The BBSome controls energy homeostasis by mediating the transport of the leptin receptor to the plasma membrane","volume":"12","author":"Guo","year":"2016","journal-title":"PLoS Genet."},{"key":"2021081104103527400_ref22","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.bone.2016.02.017","article-title":"Bardet-Biedl syndrome 3 regulates the development of cranial base midline structures","volume":"101","author":"Kawasaki","year":"2017","journal-title":"Bone"},{"key":"2021081104103527400_ref23","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0192755","article-title":"Genotypic and phenotypic characterization of the Sdccag 8Tn (sb-Tyr)2161B.CA1C2Ove mouse model","volume":"13","author":"Weihbrecht","year":"2018","journal-title":"PLoS One"},{"key":"2021081104103527400_ref24","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1038\/ng1644","article-title":"Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates","volume":"37","author":"Ross","year":"2005","journal-title":"Nat. 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A."},{"key":"2021081104103527400_ref28","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1016\/j.cub.2007.08.034","article-title":"Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease","volume":"17","author":"Davenport","year":"2007","journal-title":"Curr. Biol."},{"key":"2021081104103527400_ref29","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.123337","article-title":"Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development","volume":"4","author":"Wang","year":"2019","journal-title":"JCI Insight"},{"key":"2021081104103527400_ref30","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1093\/hmg\/ddp031","article-title":"Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling","volume":"18","author":"Seo","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"2021081104103527400_ref31","doi-asserted-by":"crossref","first-page":"7796","DOI":"10.1073\/pnas.1210192110","article-title":"Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice","volume":"110","author":"Berbari","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021081104103527400_ref32","doi-asserted-by":"crossref","first-page":"4242","DOI":"10.1073\/pnas.0711027105","article-title":"Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia","volume":"105","author":"Berbari","year":"2008","journal-title":"Proc. Natl. Acad. Sci. 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