{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T20:16:21Z","timestamp":1722975381549},"reference-count":51,"publisher":"The Endocrine Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Lin-11, Isl-1, and Mec-3 (LIM)-homeodomain (HD)-class transcription factors are critical for many aspects of mammalian organogenesis. Of these, LHX3 is essential for pituitary gland and nervous system development. Pediatric patients with mutations in coding regions of the LHX3 gene have complex syndromes, including combined pituitary hormone deficiency and nervous system defects resulting in symptoms such as dwarfism, thyroid insufficiency, infertility, and developmental delay. The pathways underlying early pituitary development are poorly understood, and the mechanisms by which the LHX3 gene is regulated in vivo are not known. Using bioinformatic and transgenic mouse approaches, we show that multiple conserved enhancers downstream of the human LHX3 gene direct expression to the developing pituitary and spinal cord in a pattern consistent with endogenous LHX3 expression. Several transferable cis elements can individually guide nervous system expression. However, a single 180-bp minimal enhancer is sufficient to confer specific expression in the developing pituitary. Within this sequence, tandem binding sites recognized by the islet-1 (ISL1) LIM-HD protein are essential for enhancer activity in the pituitary and spine, and a pituitary homeobox 1 (PITX1) bicoid class HD element is required for spatial patterning in the developing pituitary. This study establishes ISL1 as a novel transcriptional regulator of LHX3 and describes a potential mechanism for regulation by PITX1. Moreover, these studies suggest models for analyses of the transcriptional pathways coordinating the expression of other LIM-HD genes and provide tools for the molecular analysis and genetic counseling of pediatric patients with combined pituitary hormone deficiency.<\/jats:p>","DOI":"10.1210\/me.2011-1252","type":"journal-article","created":{"date-parts":[[2011,12,23]],"date-time":"2011-12-23T03:48:32Z","timestamp":1324612112000},"page":"308-319","source":"Crossref","is-referenced-by-count":12,"title":["A Distal Modular Enhancer Complex Acts to Control Pituitary- and Nervous System-Specific Expression of the LHX3 Regulatory Gene"],"prefix":"10.1210","volume":"26","author":[{"given":"Rachel D.","family":"Mullen","sequence":"first","affiliation":[{"name":"Departments of Cellular and Integrative Physiology (R.D.M., S.P., S.J.R.), Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202-5120"},{"name":"Biochemistry and Molecular Biology (R.D.M., S.P., S.J.R.), Indiana University School of Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202-5120"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soyoung","family":"Park","sequence":"additional","affiliation":[{"name":"Departments of Cellular and Integrative Physiology (R.D.M., S.P., S.J.R.), Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202-5120"},{"name":"Biochemistry and Molecular Biology (R.D.M., S.P., S.J.R.), Indiana University School of Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202-5120"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon J.","family":"Rhodes","sequence":"additional","affiliation":[{"name":"Departments of Cellular and Integrative Physiology (R.D.M., S.P., S.J.R.), Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202-5120"},{"name":"Biochemistry and Molecular Biology (R.D.M., S.P., S.J.R.), Indiana University School of Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202-5120"},{"name":"Department of Biology (S.J.R.), Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202-5120"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"key":"2020071613254413200_B1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s11033-004-7657-z","article-title":"LIM-homeodomain genes in mammalian development and human disease.","volume":"32","author":"Hunter","year":"2005","journal-title":"Mol Biol Rep"},{"key":"2020071613254413200_B2","doi-asserted-by":"crossref","first-page":"4835","DOI":"10.1242\/dev.125.23.4835","article-title":"Formation of Rathke's pouch requires dual induction from the diencephalon.","volume":"125","author":"Takuma","year":"1998","journal-title":"Development"},{"key":"2020071613254413200_B3","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1210\/er.2009-0008","article-title":"Genetic regulation of pituitary gland development in human and mouse.","volume":"30","author":"Kelberman","year":"2009","journal-title":"Endocr Rev"},{"key":"2020071613254413200_B4","first-page":"283","article-title":"LHX3 and LHX4 transcription factors in pituitary development and disease.","volume":"6","author":"Colvin","year":"2009","journal-title":"Pediatr Endocrinol Rev"},{"key":"2020071613254413200_B5","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1126\/science.278.5344.1809","article-title":"Multistep control of pituitary organogenesis.","volume":"278","author":"Sheng","year":"1997","journal-title":"Science"},{"key":"2020071613254413200_B6","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/76041","article-title":"Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency.","volume":"25","author":"Netchine","year":"2000","journal-title":"Nat Genet"},{"key":"2020071613254413200_B7","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1210\/jc.2005-2360","article-title":"Clinical case seminar: a novel LHX3 mutation presenting as combined pituitary hormonal deficiency.","volume":"91","author":"Bhangoo","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613254413200_B8","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1210\/jc.2006-2177","article-title":"Four novel mutations of the LHX3 gene cause combined pituitary hormone deficiencies with or without limited neck rotation.","volume":"92","author":"Pfaeffle","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613254413200_B9","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1093\/hmg\/ddn114","article-title":"Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss.","volume":"17","author":"Rajab","year":"2008","journal-title":"Hum Mol Genet"},{"key":"2020071613254413200_B10","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1210\/jc.2008-0325","article-title":"A novel mutation in the LIM homeobox 3 gene is responsible for combined pituitary hormone deficiency, hearing impairment, and vertebral malformations.","volume":"94","author":"Kristr\u00f6m","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613254413200_B11","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1007\/s00431-011-1393-x","article-title":"A novel mutation of LHX3 is associated with combined pituitary hormone deficiency including ACTH deficiency, sensorineural hearing loss, and short neck-a case report and review of the literature.","volume":"170","author":"Bonfig","year":"2011","journal-title":"Eur J Pediatr"},{"key":"2020071613254413200_B12","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1210\/en.2005-0970","article-title":"Two promoters mediate transcription from the human LHX3 gene: involvement of nuclear factor I and specificity protein 1.","volume":"147","author":"Yaden","year":"2006","journal-title":"Endocrinology"},{"key":"2020071613254413200_B13","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1210\/me.2005-0052","article-title":"PITX genes are required for cell survival and Lhx3 activation.","volume":"19","author":"Charles","year":"2005","journal-title":"Mol Endocrinol"},{"key":"2020071613254413200_B14","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1242\/dev.126.9.1805","article-title":"Hindlimb patterning and mandible development require the Ptx1 gene.","volume":"126","author":"Lanct\u00f4t","year":"1999","journal-title":"Development"},{"key":"2020071613254413200_B15","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1101\/gad.13.4.484","article-title":"Role of the Bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development.","volume":"13","author":"Szeto","year":"1999","journal-title":"Genes Dev"},{"key":"2020071613254413200_B16","doi-asserted-by":"crossref","first-page":"4229","DOI":"10.1242\/dev.129.18.4229","article-title":"Lhx4 and Prop1 are required for cell survival and expansion of the pituitary primordia.","volume":"129","author":"Raetzman","year":"2002","journal-title":"Development"},{"key":"2020071613254413200_B17","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1159\/000243715","article-title":"Detailed expression pattern of Foxp1 and its possible roles in neurons of the spinal cord during embryogenesis.","volume":"31","author":"Morikawa","year":"2009","journal-title":"Dev Neurosci"},{"key":"2020071613254413200_B18","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1002\/aja.1002020405","article-title":"Expression pattern of the murine LIM class homeobox gene Lhx3 in subsets of neural and neuroendocrine tissues.","volume":"202","author":"Zhadanov","year":"1995","journal-title":"Dev Dyn"},{"key":"2020071613254413200_B19","doi-asserted-by":"crossref","first-page":"2720","DOI":"10.1073\/pnas.92.7.2720","article-title":"P-Lim, a LIM homeodomain factor, is expressed during pituitary organ and cell commitment and synergizes with Pit-1.","volume":"92","author":"Bach","year":"1995","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613254413200_B20","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1089\/dna.1994.13.1163","article-title":"The mouse homeoprotein mLIM-3 is expressed early in cells derived from the neuroepithelium and persists in adult pituitary.","volume":"13","author":"Seidah","year":"1994","journal-title":"DNA Cell Biol"},{"key":"2020071613254413200_B21","doi-asserted-by":"crossref","first-page":"D88","DOI":"10.1093\/nar\/gkl822","article-title":"VISTA enhancer browser\u2014a database of tissue-specific human enhancers.","volume":"35","author":"Visel","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"2020071613254413200_B22","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/ng.650","article-title":"ChIP-Seq identification of weakly conserved heart enhancers.","volume":"42","author":"Blow","year":"2010","journal-title":"Nat Genet"},{"key":"2020071613254413200_B23","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1101\/gr.762503","article-title":"Strategies and tools for whole-genome alignments.","volume":"13","author":"Couronne","year":"2003","journal-title":"Genome Res"},{"key":"2020071613254413200_B24","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1126\/science.281.5373.60","article-title":"Going the distance: a current view of enhancer action.","volume":"281","author":"Blackwood","year":"1998","journal-title":"Science"},{"key":"2020071613254413200_B25","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1242\/dev.105.4.707","article-title":"Inducible expression of an hsp68-lacZ hybrid gene in transgenic mice.","volume":"105","author":"Kothary","year":"1989","journal-title":"Development"},{"key":"2020071613254413200_B26","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1101\/gr.5972507","article-title":"Predicting tissue-specific enhancers in the human genome.","volume":"17","author":"Pennacchio","year":"2007","journal-title":"Genome Res"},{"key":"2020071613254413200_B27","doi-asserted-by":"crossref","first-page":"D552","DOI":"10.1093\/nar\/gkh029","article-title":"GenePaint.org: an atlas of gene expression patterns in the mouse embryo.","volume":"32","author":"Visel","year":"2004","journal-title":"Nucleic Acids Res"},{"key":"2020071613254413200_B28","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1210\/mend.12.3.0073","article-title":"The pan-pituitary activator of transcription, Ptx1 (pituitary homeobox 1), acts in synergy with SF-1 and Pit1 and is an upstream regulator of the Lim-homeodomain gene Lim3\/Lhx3.","volume":"12","author":"Tremblay","year":"1998","journal-title":"Mol Endocrinol"},{"key":"2020071613254413200_B29","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0378-1119(01)00704-1","article-title":"Role of the LIM domains in DNA recognition by the Lhx3 neuroendocrine transcription factor.","volume":"277","author":"Bridwell","year":"2001","journal-title":"Gene"},{"key":"2020071613254413200_B30","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1038\/344879a0","article-title":"Insulin gene enhancer binding protein Isl-1 is a member of a novel class of proteins containing both a homeo- and a Cys-His domain.","volume":"344","author":"Karlsson","year":"1990","journal-title":"Nature"},{"key":"2020071613254413200_B31","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1242\/dev.125.6.1005","article-title":"Integrated FGF and BMP signaling controls the progression of progenitor cell differentiation and the emergence of pattern in the embryonic anterior pituitary.","volume":"125","author":"Ericson","year":"1998","journal-title":"Development"},{"key":"2020071613254413200_B32","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0092-8674(00)80985-X","article-title":"Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation.","volume":"84","author":"Pfaff","year":"1996","journal-title":"Cell"},{"key":"2020071613254413200_B33","doi-asserted-by":"crossref","first-page":"12707","DOI":"10.1523\/JNEUROSCI.3951-07.2007","article-title":"Islet-1 controls the differentiation of retinal bipolar and cholinergic amacrine cells.","volume":"27","author":"Elshatory","year":"2007","journal-title":"J Neurosci"},{"key":"2020071613254413200_B34","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1210\/me.2001-0222","article-title":"A PIT-1 homeodomain mutant blocks the intranuclear recruitment of the CCAAT\/enhancer binding protein \u03b1 required for prolactin gene transcription.","volume":"17","author":"Enwright","year":"2003","journal-title":"Mol Endocrinol"},{"key":"2020071613254413200_B35","first-page":"2442","article-title":"Mutations within Sox2\/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans.","volume":"116","author":"Kelberman","year":"2006","journal-title":"J Clin Invest"},{"key":"2020071613254413200_B36","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1210\/me.2005-0184","article-title":"The LIM-homeodomain proteins Isl-1 and Lhx3 act with steroidogenic factor 1 to enhance gonadotrope-specific activity of the gonadotropin-releasing hormone receptor gene promoter.","volume":"20","author":"Granger","year":"2006","journal-title":"Mol Endocrinol"},{"key":"2020071613254413200_B37","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1073\/pnas.1009501108","article-title":"Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo.","volume":"108","author":"Colvin","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613254413200_B38","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1126\/science.272.5264.1004","article-title":"Specification of pituitary cell lineages by the LIM homeobox gene Lhx3.","volume":"272","author":"Sheng","year":"1996","journal-title":"Science"},{"key":"2020071613254413200_B39","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.ydbio.2007.10.006","article-title":"Mechanisms underlying pituitary hypoplasia and failed cell specification in Lhx3-deficient mice.","volume":"313","author":"Ellsworth","year":"2008","journal-title":"Dev Biol"},{"key":"2020071613254413200_B40","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.modgep.2004.07.003","article-title":"Pathophysiology of syndromic combined pituitary hormone deficiency due to a LHX3 defect in light of LHX3 and LHX4 expression during early human development.","volume":"5","author":"Sobrier","year":"2004","journal-title":"Gene Expr Patterns"},{"key":"2020071613254413200_B41","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.mod.2006.06.005","article-title":"Reduced expression of the LIM-homeobox gene Lhx3 impairs growth and differentiation of Rathke's pouch and increases cell apoptosis during mouse pituitary development.","volume":"123","author":"Zhao","year":"2006","journal-title":"Mech Dev"},{"key":"2020071613254413200_B42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev-genom-082509-141651","article-title":"Genomics of long-range regulatory elements.","volume":"11","author":"Noonan","year":"2010","journal-title":"Annu Rev Genomics Hum Genet"},{"key":"2020071613254413200_B43","doi-asserted-by":"crossref","first-page":"3499","DOI":"10.1128\/MCB.02170-06","article-title":"Analysis of the H19ICR insulator.","volume":"27","author":"Yoon","year":"2007","journal-title":"Mol Cell Biol"},{"key":"2020071613254413200_B44","doi-asserted-by":"crossref","first-page":"W280","DOI":"10.1093\/nar\/gkh355","article-title":"ECR Browser: a tool for visualizing and accessing data from comparisons of multiple vertebrate genomes.","volume":"32","author":"Ovcharenko","year":"2004","journal-title":"Nucleic Acids Res"},{"key":"2020071613254413200_B45","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1101\/gr.229102","article-title":"The human genome browser at UCSC.","volume":"12","author":"Kent","year":"2002","journal-title":"Genome Res"},{"key":"2020071613254413200_B46","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1101\/gr.225502","article-title":"rVista for comparative sequence-based discovery of functional transcription factor binding sites.","volume":"12","author":"Loots","year":"2002","journal-title":"Genome Res"},{"key":"2020071613254413200_B47","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1093\/nar\/gkg108","article-title":"TRANSFAC: transcriptional regulation, from patterns to profiles.","volume":"31","author":"Matys","year":"2003","journal-title":"Nucleic Acids Res"},{"key":"2020071613254413200_B48","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/jcp.21010","article-title":"Transgenic mice expressing LHX3 transcription factor isoforms in the pituitary: effects on the gonadotrope axis and sex-specific reproductive disease.","volume":"212","author":"Savage","year":"2007","journal-title":"J Cell Physiol"},{"key":"2020071613254413200_B49","doi-asserted-by":"crossref","first-page":"7001","DOI":"10.1128\/MCB.19.10.7001","article-title":"Multifunctional role of the Pitx2 homeodomain protein C-terminal tail.","volume":"19","author":"Amendt","year":"1999","journal-title":"Mol Cell Biol"},{"key":"2020071613254413200_B50","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.2337\/db08-0987","article-title":"Islet-1 is required for the maturation, proliferation, and survival of the endocrine pancreas.","volume":"58","author":"Du","year":"2009","journal-title":"Diabetes"},{"key":"2020071613254413200_B51","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1128\/MCB.23.6.1968-1982.2003","article-title":"Dominant negative dimerization of a mutant homeodomain protein in Axenfeld-Rieger syndrome.","volume":"23","author":"Saadi","year":"2003","journal-title":"Mol Cell Biol"}],"container-title":["Molecular Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/mend\/article-pdf\/26\/2\/308\/8935103\/mend0308.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/mend\/article-pdf\/26\/2\/308\/8935103\/mend0308.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T21:48:27Z","timestamp":1640123307000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/mend\/article\/26\/2\/308\/2614878"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,2,1]]},"references-count":51,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2012,2,1]]}},"URL":"https:\/\/doi.org\/10.1210\/me.2011-1252","relation":{},"ISSN":["0888-8809","1944-9917"],"issn-type":[{"value":"0888-8809","type":"print"},{"value":"1944-9917","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,2,1]]}}}