Role of the LIM domains in DNA recognition by the Lhx3 neuroendocrine transcription factor

Bridwell, JeAnne L.; Price, Jeffrey R.; Parker, Gretchen E.; Schiller, Amy McCutchan; Sloop, Kyle W.; Rhodes, Simon J.

doi:10.1016/s0378-1119(01)00704-1

Cited by 39 publications

(50 citation statements)

References 29 publications

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“…5). Additionally, as expected, these binding sites contain a putative binding motif, TAAT/ATTA, in the forward or reverse orientation or an AT-rich sequence, but the reported conservation of the consensus binding sequence of Lhx3 (5'-aaTTAATTAat-3') was absent [17].It has been reported that Lhx3 acts as a monomer binding to the minor groove with remarkable DNA bending of 62° [17]. Correspondingly, DNase I footprinting revealed increased DNase I sensitivity (Fig.…”

supporting

confidence: 58%

Regulation of Porcine Pituitary Glycoprotein Hormone Alpha Subunit Gene with LIM-Homeobox Transcription Factor Lhx3

Sugiyama

Ishikawa

Katō

et al. 2009

Journal of Reproduction and Development

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Abstract. The aim of this study was to characterize the promoter activity of the porcine pituitary glycoprotein hormone common alpha gene (Cga) promoter (-1059/+12) and the role of LIM homeodomain transcription factor Lhx3. A transfection assay using Chinese hamster ovary (CHO) cells showed that the -1059/-101 region of the Cga promoter definitely responds to Lhx3 and that the -1059/-240 region exhibits a high basal transcriptional level in a pituitaryderived cell line, LβT2. A DNA binding and DNase I footprinting assay demonstrated that Lhx3 has seven binding sites in the -1059/+12 region of Cga, including a pituitary glycoprotein hormone basal element (PGBE) known as a LIM homeodomain factor-binding site. A transfection assay of the sequence of Lhx3-binding sites fused with minimal promoter vector confirmed their Lhx3-dependent stimulations in LβT2 cells. RT-PCR analysis of porcine pituitary ontogeny demonstrated that porcine Lhx3 showed striking changes of expression in both sexes during the fetal period but a stable high level of expression after birth. Thus, the porcine Cga promoter is regulated by Lhx3 through seven sites in the distal and proximal regions. Key words: Gene regulation, Lhx3, LIM homeodomain, Pituitary glycoprotein hormone (J. Reprod. Dev. 55: [425][426][427][428][429][430][431][432] 2009) ituitary glycoprotein hormone common alpha subunit (αGSU) plays an indispensable role as a common counterpart by forming a heterodimer with the specific β subunits of follicle stimulating hormone (FSH), luteinizing hormone (LH) and thyroid stimulating hormone (TSH) [1]. It is expressed differently in gonadotrope cells producing FSH and LH and in thyrotrope cells producing TSH under cell-specific mechanisms [2]. Understanding the molecular basis of αGSU gene (Cga) regulation would be of scientific interest.We previously cloned and determined up to the -1059 bp upstream sequence of the porcine Cga [3] and demonstrated that transcription factors, Ptx1, Prop1 and Msx1, are potentially capable of modulating this gene [4][5][6]. Several studies have demonstrated that many cis-elements are important for the response of the extracellular signal and cell type-or tissue-specific expression of Cga [7,8]. These cis-elements include pituitary glycoprotein hormone basal element (PGBE, [9], gonadotrope-specific element (GSE, [10], cAMP-responsive element (CRE) [11][12][13], GnRH responsive element [14], upstream regulatory element (URE) [15], trophoblast-specific element (TSE) [16] and alpha basal elements 1 and 2 (alpha BE1 and BE2) [15]. Transcription factors, Lhx2 [9] and Lhx3 [17] for PGBE, Sf1 for GSE [10], CRE binding protein (Creb) for CRE [13,18] and Gata2 for GATA element [19], participate in cell-type or tissue-specific regulation. Thus, in the proximal region, expression of Cga is controlled by various trans-acting factors through binding to the discrete elements.Recently, we reported a prominent transcription activity of the porcine Cga promoter over the PGBE [4]. The distal region of the porcine Cga prom...

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confidence: 58%

Regulation of Porcine Pituitary Glycoprotein Hormone Alpha Subunit Gene with LIM-Homeobox Transcription Factor Lhx3

Sugiyama

Ishikawa

Katō

et al. 2009

Journal of Reproduction and Development

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“…M2-LHX3 lacks the amino terminus and LIM domains found in LHX3a and LHX3b. The three LHX3 isoforms display different biochemical and functional properties (Sloop et al, 1999;Parker et al, 2000;Bridwell et al, 2001;Sloop et al, 2001a;Parker et al, 2005;Yaden et al, 2005).…”

Section: Lhx3mentioning

confidence: 99%

Roles of the LHX3 and LHX4 LIM-homeodomain factors in pituitary development

Mullen

Colvin

Hunter

et al. 2007

Molecular and Cellular Endocrinology

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The LHX3 and LHX4 LIM-homeodomain transcription factors play essential roles in pituitary gland and nervous system development. Mutations in the genes encoding these regulatory proteins are associated with combined hormone deficiency diseases in humans and animal models. Patients with these diseases have complex syndromes involving short stature, and reproductive and metabolic disorders. Analyses of the features of these diseases and the biochemical properties of the LHX3 and LHX4 proteins will facilitate a better understanding of the molecular pathways that regulate the development of the specialized hormone-secreting cells of the mammalian anterior pituitary gland.

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“…Expression constructs for ISL1, NeuroM, and E47 were generous gifts from Dr. Gordon Gill (University of California San Diego), Dr. Teri Belecky-Adams (IUPUI), and Dr. Stephen Konieczny (Purdue University), respectively. The FSHβ, TSHβ, PIT1 EP0.5 enhancer/ promoter, and LHX3 consensus binding site (3x LBC) luciferase reporter plasmids were as described (Drolet et al, 1991;Rhodes et al, 1993;Bridwell et al, 2001;West et al, 2004). The M250 region of the Hb9 gene (Thaler et al, 2002) was amplified from C57black6 mouse genomic DNA by the PCR using the following primers: 5′-cgcggatcctttctcgcaacacttccaggctcag-3′, 5′-gaagatctcccctactctccctacagtctctgg-3′.…”

Section: Plasmid Construction and Site-directed Mutagenesismentioning

confidence: 99%

“…The M250 region of the Hb9 gene (Thaler et al, 2002) was amplified from C57black6 mouse genomic DNA by the PCR using the following primers: 5′-cgcggatcctttctcgcaacacttccaggctcag-3′, 5′-gaagatctcccctactctccctacagtctctgg-3′. This amplicon was ligated into the BamHI site of the 36 bp PRL minimal promoter/luciferase reporter gene (Bridwell et al, 2001). A similar Hb9 enhancer plasmid was a generous gift from Dr. Samuel Pfaff (Salk Institute).…”

Section: Plasmid Construction and Site-directed Mutagenesismentioning

confidence: 99%

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Mutations in the LHX3 gene cause dysregulation of pituitary and neural target genes that reflect patient phenotypes

Savage

Hunter

Clark-Sturm

et al. 2007

Gene

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The LHX3 LIM-homeodomain transcription factor is required for correct development of the mammalian pituitary gland and spinal motoneurons. Mutations in the LHX3 gene underlie complex diseases featuring combined anterior pituitary hormone deficiency and, in specific cases, loss of neck rotation considered to result from nervous system abnormalities. The molecular basis for LHX3 protein actions in both normal and aberrant pituitary and nervous system development is poorly understood. In this study, the gene regulatory abilities of mutant LHX3 proteins associated with distinct types of diseases (LHX3a A210V, LHX3a E173Ter, and LHX3a W224Ter) were investigated. The capacity of these proteins to activate pituitary hormone and transcription factor gene promoters, nervous system target genes, and to localize to the nucleus of pituitary cells was measured. Consistent with the symptoms of patients with these mutations, the abnormal proteins displayed diminished capacities to activate the promoters of genes expressed in the pituitary gland. On nervous system promoters, several mutant proteins retained some activity. The ability of the mutant proteins to concentrate in the nucleus of pituitary cells was correlated with the retention of defined nuclear localization signals in the protein sequence, except for the E173Ter protein which unexpectedly localizes to the nucleus, likely due to the insertion of cryptic nuclear localization signals by a frame shift caused by the mutation. This study extends the molecular characterization of the severe neuroendocrine diseases associated with LHX3 gene mutations.

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Role of the LIM domains in DNA recognition by the Lhx3 neuroendocrine transcription factor

Cited by 39 publications

References 29 publications

Regulation of Porcine Pituitary Glycoprotein Hormone Alpha Subunit Gene with LIM-Homeobox Transcription Factor Lhx3

Regulation of Porcine Pituitary Glycoprotein Hormone Alpha Subunit Gene with LIM-Homeobox Transcription Factor Lhx3

Roles of the LHX3 and LHX4 LIM-homeodomain factors in pituitary development

Mutations in the LHX3 gene cause dysregulation of pituitary and neural target genes that reflect patient phenotypes

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