Affinage

LHX3

LIM/homeobox protein Lhx3 · UniProt Q9UBR4

Length
397 aa
Mass
43.4 kDa
Annotated
2026-06-10
84 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LHX3 is a LIM-homeodomain transcription factor that governs both pituitary gland development and spinal motor neuron/interneuron specification, acting as a combinatorial, context-dependent transcriptional regulator (PMID:8638120, PMID:12150931, PMID:22343290). In the pituitary it is essential for proliferation and differentiation of all anterior/intermediate lobe lineages except corticotrophs, and its loss arrests Rathke's pouch growth and disrupts dorsal-ventral patterning, cell survival, and lineage-specifying factor expression (PMID:8638120, PMID:18037398). It binds an AT-rich consensus site as a monomer through its homeodomain, bending DNA in a manner consistent with an architectural role; the LIM domains lower affinity without altering specificity, and homeodomain deletion abolishes both DNA binding and target activation (PMID:11602361, PMID:11255008). LHX3 directly activates pituitary hormone gene promoters—alpha-glycoprotein subunit, TSHbeta, prolactin, FSHbeta, and the GnRH receptor—often synergizing with Pit-1 and, at the GnRH-R promoter, with ISL1 and SF-1 through dedicated LIM response elements (PMID:10598593, PMID:15271874, PMID:10195693, PMID:16613990, PMID:9714537). In the spinal cord, LHX3 partners with the cofactor NLI/Ldb1 to promote V2 interneuron fate, but ISL1 competes for NLI and redirects LHX3 onto a high-affinity site in its own C-terminus, forming the ISL1-LHX3 motor neuron-specifying complex that induces motor neuron genes while suppressing interneuron programs (PMID:12150931, PMID:22343290). This complex sustains itself through an autoregulatory loop—directly activating Isl1, Lhx3, and Lmo4 (LMO4 sequestering LHX3 away from the interneuron complex)—and induces miR-218 as a downstream effector that represses interneuron transcripts (PMID:28451636, PMID:26212498). LHX3 function is further tuned post-translationally by PKC/CKII phosphorylation at five mapped residues and by promoter DNA methylation and histone modification, and it interacts with the INHAT components LANP and TAF-1beta to modulate chromatin-based regulation at target genes (PMID:15517599, PMID:24183897, PMID:23861948). Loss-of-function LHX3 mutations cause combined pituitary hormone deficiency, and patient and mouse mutants reveal that pituitary and nervous-system functions are molecularly separable—the C-terminal activation region being specifically required for pituitary gene activation (PMID:17616267, PMID:21149718, PMID:22132174).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1996 High

    Established LHX3 as essential for pituitary organogenesis, defining the developmental process it controls before any molecular mechanism was known.

    Evidence Targeted gene disruption in mice with pituitary lineage phenotyping

    PMID:8638120

    Open questions at the time
    • Did not define DNA targets or partner proteins
    • Corticotroph-sparing selectivity left mechanistically unexplained
  2. 1998 Medium

    Placed LHX3 within a transcriptional cascade and identified its first direct target, showing it acts downstream of Ptx1 and activates the prolactin promoter independently of Pit-1.

    Evidence Antisense knockdown in alphaT3-1 cells; EMSA and RT-PCR on prolactin promoter in AtT20 cells

    PMID:9514159 PMID:9714537

    Open questions at the time
    • Single-lab promoter-binding data
    • Hierarchy inferred from knockdown rather than genetics at this stage
  3. 1999 High

    Defined isoform diversity and physical partnership with Pit-1, showing N-terminal sequences modulate DNA binding and that LHX3 synergizes with Pit-1 on hormone promoters.

    Evidence Reporter, DNA-binding, and localization assays on hLHX3a/b; Co-IP and reporter assays with porcine Lhx3

    PMID:10195693 PMID:10598593

    Open questions at the time
    • In vivo relevance of isoform ratios not established
    • Co-IP without reciprocal mapping for Pit-1 contact surface
  4. 2001 High

    Resolved the architecture of LHX3 as a DNA-binding transcription factor: it binds AT-rich DNA as a monomer and bends it, the homeodomain is required for binding and activity, and N-terminal/translation variants tune output.

    Evidence Site selection, EMSA, footprinting, DNA-bending and reporter assays; in vitro translation and domain-swap experiments

    PMID:11470784 PMID:11602361

    Open questions at the time
    • No co-crystal of LHX3 homeodomain with DNA
    • Functional role of DNA bending in vivo not demonstrated
  5. 2000 High

    Connected subcellular targeting to function by mapping homeodomain-encoded NLS and nuclear matrix targeting signals whose mutation alters transcriptional activity.

    Evidence Fluorescent fusion imaging, functional NLS mapping, and nuclear fractionation

    PMID:10818088

    Open questions at the time
    • Import machinery recognizing the signals not identified
    • Significance of nuclear matrix association for target gene choice unresolved
  6. 2002 High

    Defined the core mechanistic switch underlying LHX3's dual identity: NLI binding drives V2 interneuron fate, while ISL1 competition for NLI redirects LHX3 into a motor neuron-specifying complex.

    Evidence Reciprocal pulldown/Co-IP and in vivo functional assays in chick neural tube

    PMID:12150931

    Open questions at the time
    • Quantitative stoichiometry not yet resolved
    • Downstream target genes of each complex not yet enumerated
  7. 2001 High

    Linked a disease mutation to a discrete molecular defect, showing Y116C/Y114C abolishes cofactor (SLIM/CLIM) binding and transactivation while sparing DNA binding and NLI interaction.

    Evidence Mobility shift, reporter, and protein interaction assays on patient mutant

    PMID:11255008 PMID:11279219

    Open questions at the time
    • Mechanism of how cofactor loss blocks activation not yet structurally explained at this stage
  8. 2004 High

    Detailed promoter logic at FSHbeta, showing multiple LHX3 sites including essential proximal elements and establishing paralog specificity (LHX4 substitutes, Drosophila LIM3 does not).

    Evidence Reporter assays, mutagenesis, EMSA, dominant-negative experiments in gonadotrope cells

    PMID:15271874

    Open questions at the time
    • Cofactor requirements at individual sites not dissected
    • Activin-LHX3 relationship only partially defined
  9. 2005 High

    Anchored the upstream regulatory hierarchy genetically and post-translationally: PITX1/PITX2 are required for LHX3 expression, and PKC/CKII phosphorylation at five mapped residues tunes LHX3 activity.

    Evidence Double-knockout mouse epistasis; mass-spectrometry phosphosite mapping with kinase overexpression and mutagenesis

    PMID:15517599 PMID:15761027

    Open questions at the time
    • Physiological signals activating PKC/CKII toward LHX3 unknown
    • Phosphorylation mechanism of activity reduction unresolved (DNA binding/partners unaffected)
  10. 2005 High

    Defined the dual GC-rich promoters driving LHX3 isoforms and their trans-regulators SP1 and NFI.

    Evidence Deletion analysis, EMSA, Southwestern blot, and ChIP

    PMID:16179410

    Open questions at the time
    • Tissue-specific control of isoform choice not fully explained
  11. 2006 High

    Extended LHX3's developmental role to dorsal-ventral patterning and cell survival, and broadened its hormone-promoter repertoire to the GnRH receptor through LHX3/ISL1/SF-1 cooperation.

    Evidence Lhx3-null mouse marker/cell-death analysis; transfection, EMSA, transgenic and dominant-negative assays on GnRH-R promoter

    PMID:16613990 PMID:18037398

    Open questions at the time
    • Direct vs indirect basis of patterning defects not separated
    • Combinatorial code with SF-1 not structurally defined
  12. 2012 High

    Provided the structural explanation for the Y114C disease mechanism: it destabilizes the LIM2 hydrophobic core without altering zinc ligation, reducing affinity for both Ldb1 and Isl1.

    Evidence NMR spectroscopy with mutagenesis and SAXS confirmation of the Ldb1-Lhx3 complex in solution

    PMID:22848397

    Open questions at the time
    • Full DNA-bound complex geometry not yet captured
  13. 2012 High

    Showed the ISL1-LHX3 complex is a self-sufficient motor neuron program, defining its transcriptome and the requirement for equimolar stoichiometry and the LHX3 LIM domain.

    Evidence ES cell differentiation, chick electroporation, RNA-seq, and domain-deletion analysis

    PMID:22343290

    Open questions at the time
    • Direct genomic binding sites not yet mapped at this stage
  14. 2010 High

    Demonstrated domain-level separability of LHX3's two tissue roles, with the C-terminus specifically required for pituitary but not nervous-system function.

    Evidence W227ter knockin mouse with endocrine and neurological phenotyping; hypomorphic mouse marker analysis

    PMID:16859901 PMID:21149718

    Open questions at the time
    • Why the C-terminus is dispensable for motor neuron output mechanistically unexplained
  15. 2013 High

    Identified the chromatin-modifying machinery LHX3 engages, linking it to the INHAT complex, and extended FSHB target characterization to a transcription-altering human SNP.

    Evidence Pull-down/MS interactor ID, domain mapping, ChIP and reporter assays for INHAT; EMSA and reporter assays for the -211 FSHB SNP

    PMID:23766128 PMID:23861948

    Open questions at the time
    • Functional consequence of INHAT recruitment on histone acetylation at LHX3 targets not directly measured
    • SNP effect not tested in vivo
  16. 2013 Medium

    Established epigenetic silencing of LHX3 via DNA methylation and histone deacetylation in non-expressing cells, with MeCP2 recruitment.

    Evidence Demethylating/HDAC-inhibitor treatment, bisulfite sequencing, and ChIP

    PMID:24183897

    Open questions at the time
    • Single-lab data
    • Causal sequence of methylation vs histone marks not resolved
  17. 2015 High

    Identified miR-218 as a direct downstream effector of the ISL1-LHX3 complex that enforces motor neuron identity by repressing interneuron transcripts.

    Evidence Chick electroporation, ES cell differentiation, RISC-trap, reporter assays, and ChIP

    PMID:26212498

    Open questions at the time
    • Full set of miR-218 targets relevant in vivo not exhaustively defined
  18. 2017 High

    Defined the autoregulatory architecture stabilizing motor neuron fate: the complex directly activates Isl1, Lhx3, and Lmo4, with LMO4 sequestering LHX3 from the interneuron complex.

    Evidence ChIP in chick and mouse embryos with reporter and loss-of-function assays

    PMID:28451636

    Open questions at the time
    • Quantitative dynamics of the feedback loop not modeled
  19. 2020 High

    Provided biophysical detail of how ISL1 and LHX3 DNA-binding modules coordinate on DNA to direct motor neuron gene expression.

    Evidence EMSA, surface plasmon resonance, and SAXS on DNA-bound ISL1-LHX3 species

    PMID:33458649

    Open questions at the time
    • High-resolution co-crystal of full DNA-bound complex still lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • How upstream signaling controls LHX3 phosphorylation status, and how the INHAT/chromatin interactions and DNA-bending architecture mechanistically couple to specific target gene outputs in vivo, remains open.
  • No identified signaling input driving PKC/CKII phosphorylation of LHX3
  • Direct effect of LHX3 on histone acetylation at endogenous targets unmeasured
  • No high-resolution structure of LHX3 homeodomain bound to its DNA element

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 4 GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0005634 nucleus 1 GO:0005654 nucleoplasm 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 2
Partners
ANP32A/LANPISL1LDB1/NLILMO4PITX1POU1F1/PIT-1SET/TAF-1BETASF-1
Complex memberships
INHAT complexIsl1-Lhx3 complexLhx3-NLI/Ldb1 complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Targeted gene disruption of Lhx3 in mice showed it is essential for differentiation and proliferation of pituitary cell lineages (all except corticotrophs). Rathke's pouch formed but failed to grow and differentiate; anterior and intermediate lobes were absent. Targeted gene disruption (knockout mouse) Science High 8638120
2002 Lhx3 binds directly to the LIM cofactor NLI to trigger V2 interneuron differentiation. In motor neurons, Isl1 competes for NLI binding, displacing Lhx3 to a high-affinity binding site on the C-terminal region of Isl1, converting Lhx3 from an interneuron-promoting to a motor neuron-promoting factor via cell-type-specific LIM complex formation. In vivo function assays and protein interaction assays (pulldown, co-IP) Cell High 12150931
1999 Two human LHX3 isoforms (hLHX3a and hLHX3b) differ in amino-terminal sequences; hLHX3b's unique N-terminal domain acts as a transferable inhibitor that reduces DNA binding and gene activation. hLHX3a trans-activates alpha-glycoprotein subunit promoter and synergizes with Pit-1 on TSHbeta gene more effectively than hLHX3b. Reporter gene assays, DNA binding assays, nuclear localization studies Molecular endocrinology High 10598593
2001 The LHX3b-specific N-terminal domain is a transferable inhibitory module that reduces DNA binding and transcriptional activation by homeodomain proteins. An alternative internal translation initiation codon generates M2-LHX3, which lacks LIM domains and N-terminus but retains the C-terminal activation domain, binds DNA better than LHX3a/b, and is transcriptionally active. Transfection assays, in vitro translation, domain transfer experiments The Journal of biological chemistry High 11470784
2001 LHX3 binds an AT-rich consensus DNA sequence as a monomer with minor groove contacts. The LIM domains reduce DNA binding affinity but do not affect specificity. The Lhx3 binding consensus site confers Lhx3-dependent transcriptional activation to heterologous promoters, and DNA is bent upon Lhx3 binding, consistent with an architectural transcription factor role. Site selection, EMSA, DNase I footprinting, transcriptional reporter assays, DNA bending assays Gene High 11602361
2000 Lhx3 is found in both the nucleoplasm and nuclear matrix. Three nuclear localization signals (NLS) were mapped within the homeodomain and one in the carboxyl terminus; signals work combinatorially. The homeodomain serves as the nuclear matrix targeting sequence. Mutation of NLS signals within the homeodomain inhibited transcriptional function, while mutation of the C-terminal NLS activated Lhx3. Fluorescent fusion protein imaging, functional NLS mapping, nuclear fractionation The Journal of biological chemistry High 10818088
2001 LHX3 missense mutation Y116C (human; Y114C in mouse) inhibits transcriptional activation from target genes but does not prevent DNA binding or interaction with NLI. However, it essentially abolishes binding to the co-activator/adapter selective LIM-binding protein (SLIM/CLIM) and may modestly reduce binding to Pit-1. Mobility shift assays, transfection reporter assays, protein interaction studies The Journal of biological chemistry High 11255008 11279219
2001 LHX3 proteins lacking the homeodomain (truncation mutants) do not bind DNA and cannot activate pituitary gene promoters. The Y116C missense mutation inhibits transcriptional activation but preserves DNA binding and protein interactions with NLI and Pit-1. Reporter gene assays, EMSA, protein interaction assays Gene High 11255008
1998 Ptx1 acts upstream of Lhx3/Lim3 in a transcriptional cascade; antisense RNA knockdown of Ptx1 in alphaT3-1 cells showed that Lhx3/Lim3 expression is highly dependent on Ptx1. Antisense RNA knockdown, reporter gene assays Molecular endocrinology Medium 9514159
2005 PITX1 and PITX2 double knockout mice fail to express LHX3, placing these PITX genes upstream of LHX3 in pituitary development by genetic epistasis. Double knockout mouse genetics (epistasis) Molecular endocrinology High 15761027
2004 LHX3 activates the FSHbeta promoter through at least six binding sites, including three proximal sites essential for both LHX3 induction and basal promoter activity in gonadotrope cells. FSHbeta promoter responses to activin do not require LHX3 gene induction. The related LHX4 can also activate the FSHbeta promoter, but Drosophila LIM3 cannot. Transfection reporter assays in gonadotrope and heterologous cells, site-directed mutagenesis, EMSA, dominant-negative experiments Endocrinology High 15271874
1999 Porcine Lhx3 protein interacts with Pit-1 in solution and with NLI/Lbd1/CLIM; it synergistically induces transcription from prolactin enhancer/promoter reporter genes in cooperation with Pit-1, and binds to target sites in the alpha-glycoprotein gene upstream sequence. Co-immunoprecipitation, EMSA, transfection reporter assays Molecular and cellular endocrinology Medium 10195693
2005 LHX3 protein is phosphorylated at five amino acid residues: T63 and S71 in LIM domain 1, and Y227, S234, S238 in the carboxyl terminus. Protein kinase C and casein kinase II can phosphorylate LHX3, and their overexpression reduces LHX3 transcriptional activity. Non-modifiable substitutions at these sites significantly reduced LHX3 transcriptional activity without affecting interactions with NLI, PIT1, MRG1, or DNA binding. Mass spectrometry phosphorylation mapping, kinase overexpression, site-directed mutagenesis, reporter assays Journal of cellular biochemistry High 15517599
2006 LHX3 deficiency in mice causes increased cell death early in pituitary development (in TPIT-expressing corticotrope regions), dorsal ectopic expression of gonadotrope transcription factors SF1 and ISL1 (without gonadotropin expression), and loss of NOTCH2 expression at the dorsal-ventral pituitary boundary. This implicates LHX3 in maintaining dorsal-ventral patterning, cell survival, and corticotrope-specific transcription factor expression. Analysis of Lhx3 null mice: cell death assays, IHC for transcription factor markers, in vivo expression analysis Developmental biology High 18037398
2005 Two conserved, TATA-less, GC-rich promoters drive transcription of hLHX3a and hLHX3b mRNAs. Specificity protein 1 (SP1) regulates both promoters through GC box interactions. Nuclear factor I (NFI) is critical for hLHX3b promoter function through interaction with a distal intronic element. Deletion analysis, transfection assays, site-directed mutagenesis, EMSA, Southwestern blot, chromatin immunoprecipitation Endocrinology High 16179410
2011 A distal downstream enhancer (~180 bp minimal element) contains tandem ISL1-binding sites essential for LHX3 expression in both pituitary and spinal cord, and a PITX1 binding element required for spatial patterning in the pituitary. ISL1 is identified as a novel transcriptional regulator of the LHX3 gene. Transgenic mouse reporter assays, bioinformatics, site-directed mutagenesis Molecular endocrinology High 22194342
2012 The Isl1-Lhx3 complex specifies spinal motor neurons with high specificity by inducing motor neuron gene transcription and concomitantly suppressing interneuron differentiation programs. An equimolar ratio of Isl1 and Lhx3 and the LIM domain of Lhx3 are crucial for MN generation without upregulating interneuron genes. RNA-seq analysis revealed the motor neuron transcriptome induced by the complex. Stem cell differentiation (embryonic stem cells), chick neural tube electroporation, RNA-seq, domain deletion analysis PNAS High 22343290
2013 LHX3 binds to an 11-bp element in the human FSHB promoter containing the -211 SNP site. The G/T SNP at -211 reduces LHX3 binding affinity and decreases FSHB transcription in gonadotrope cells. EMSA, competitive binding assays, reporter gene assays in gonadotrope cells Endocrinology High 23766128
2012 NMR analysis of LHX3(Y114C) mutation shows it does not alter zinc-ligation properties but causes structural rearrangement of the hydrophobic core of the LIM2 domain, destabilizing it and reducing affinity for both Ldb1 and Isl1. Small-angle X-ray scattering confirmed that the Ldb1-Lhx3 complex in solution matches the NMR-determined ensemble structure with two well-defined halves connected by a flexible linker. NMR spectroscopy, small-angle X-ray scattering (SAXS) PloS one High 22848397
2013 LHX3 interacts with LANP/pp32 and TAF-1β/SET, components of the inhibitor of histone acetyltransferase (INHAT) complex. These interactions were mapped to specific protein domains. ChIP experiments showed LANP and TAF-1β are associated with LHX3 target genes in pituitary cells, and altering LANP/TAF-1β levels affects LHX3-mediated pituitary gene regulation. Biochemical pull-down, mass spectrometry, domain mapping, chromatin immunoprecipitation, reporter gene assays PloS one High 23861948
2015 The Isl1-Lhx3 complex directly upregulates expression of miR-218 in developing spinal cord. miR-218 is required for motor neuron differentiation and acts downstream of Isl1-Lhx3 by repressing transcripts that promote interneuron programs. miR-218 activity is required for Isl1-Lhx3 to effectively induce motor neurons and suppress interneuron fates. Chick neural tube electroporation, mouse embryonic stem cell differentiation, RISC-trap screens, in vivo reporter assays, ChIP Nature communications High 26212498
2017 The Isl1-Lhx3 complex directly activates transcription of its own component genes (Isl1 and Lhx3) and Lmo4 through specific genomic loci in embryonic motor neurons, establishing a potent autoregulatory feedback loop. LMO4, induced by the complex, blocks formation of the V2 interneuron-specifying Lhx3 complex, increasing the pool of Lhx3 available for the Isl1-Lhx3 complex. ChIP in chick and mouse embryos, reporter gene assays, loss-of-function studies eNeuro High 28451636
2008 SOX2 is capable of binding to and activating transcription of the LHX3 proximal promoter in vitro, suggesting a regulatory interaction between SOX2 and LHX3 in inner ear and pituitary development. In vitro transcription activation assay, promoter binding assay Human molecular genetics Medium 18407919
2010 In mice, reduced Lhx3 expression causes increased cell apoptosis in Rathke's pouch and loss of Islet1 and Calbindin marker expression, placing Lhx3 downstream of Pitx factors in a transcriptional cascade controlling pituitary growth and early cell differentiation. Targeted insertion hypomorphic mouse model, in vivo marker expression analysis, cell death assays Mechanisms of development Medium 16859901
2010 A premature stop codon in the Lhx3 C-terminus (W227ter mouse model) results in loss of pituitary gene activation but does not affect nervous system function, demonstrating that the C-terminal region of LHX3 is required specifically for pituitary gene activation but not for viability or motor neuron function, and that the in vivo actions of LHX3 in different tissues are molecularly separable. Targeted knockin mouse model, endocrine phenotyping, behavioral/neurological assessment PNAS High 21149718
2006 LHX3 and ISL-1 together with steroidogenic factor 1 (SF-1) activate the GnRH receptor gene promoter through specific LIM response elements. Deletion of the LIM response element decreases promoter activity. Lhx5 and Lhx9 cannot substitute, confirming specificity. In gonadotrope cells, LIM-HD protein activity depends upon SF-1 binding. Transfection assays, EMSA, promoter deletion analysis, transgenic mouse in vivo monitoring, dominant-negative experiments Molecular endocrinology High 16613990
1998 Lhx3 (mLIM3) directly binds to a conserved 15-mer element (nts -218 to -204) in the prolactin promoter and induces prolactin mRNA expression in AtT20 corticotroph cells via a Pit-1/GHF-1-independent pathway. Stable transfection, gel retardation (EMSA), RT-PCR FEBS letters Medium 9714537
2012 A LIM-only protein resulting from a splice-site mutation in LHX3 (c.252-3C>G, producing protein with only one LIM domain) exerts a dominant-negative effect over wild-type LHX3 in coexpression studies. In vitro coexpression (dominant-negative) reporter assays The Journal of clinical endocrinology and metabolism Medium 22238406
2008 A stable intramolecular complex comprising the LIM domains of Lhx3 tethered to a peptide region of Isl1 was crystallized, yielding monoclinic crystals diffracting to 2.05 Å resolution, providing a structural basis for the Lhx3-Isl1 interaction. Protein crystallization, X-ray diffraction Acta crystallographica Section F Medium 18391431
2017 C. elegans orthologs of LHX3 (CEH-14) and ISL1 (LIM-7) physically interact via yeast two-hybrid. The structure of the CEH-14 LIM domains/LIM-7 LIM-interaction domain complex closely resembles vertebrate Lhx3/Isl1, though mutagenic analysis revealed some differences in binding mechanisms. The two proteins are co-expressed in a small subset of C. elegans neurons. Yeast two-hybrid, structural characterization, mutagenesis, fluorescent reporter expression analysis Scientific reports Medium 28676648
2020 ISL1 and LHX3 show markedly different DNA-binding behaviors both alone and in complexes. SAXS structural characterization of DNA-bound ISL1-LHX3-containing species, combined with EMSA and SPR, reveals how the two DNA-binding modules coordinate to regulate gene expression and direct spinal motor neuron development. EMSA, surface plasmon resonance (SPR), small-angle X-ray scattering (SAXS) Journal of structural biology: X High 33458649
2013 DNA methylation contributes to the silencing of the Lhx3 gene in pituitary cells that do not normally express it. Treatment with a demethylating agent alone or combined with a histone deacetylase inhibitor activates Lhx3 expression. MeCP2 methyl-binding protein was found associated with Lhx3 promoter regions by ChIP, indicating crosstalk between DNA methylation and histone modification in Lhx3 regulation. Chemical demethylation (5-aza-2'-deoxycytidine), HDAC inhibition, bisulfite sequencing, chromatin immunoprecipitation Gene Medium 24183897
2011 In German shepherd dogs, a deletion of one of six 7-bp repeats in LHX3 intron 5 reduces the intron to 68 bp, preventing efficient splicing. This results in either exon 5 skipping or intron 5 retention, producing aberrant mRNA transcripts and causing combined pituitary hormone deficiency (pituitary dwarfism). Exon trapping assay, bisulfite-RT-PCR splicing analysis, genomic sequencing PloS one High 22132174
2007 LHX3 mutations (E173ter, W224ter, A210V) show diminished capacity to activate pituitary hormone gene promoters consistent with patient hormone deficiencies. Several mutant proteins retained some activity on nervous system promoters. Nuclear localization of mutant proteins correlated with retention of defined NLS sequences, except E173ter which unexpectedly localizes to nucleus via cryptic NLS from frameshift. Reporter gene assays, nuclear localization imaging in pituitary cells Gene Medium 17616267

Source papers

Stage 0 corpus · 84 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Specification of pituitary cell lineages by the LIM homeobox gene Lhx3. Science (New York, N.Y.) 370 8638120
2002 LIM factor Lhx3 contributes to the specification of motor neuron and interneuron identity through cell-type-specific protein-protein interactions. Cell 298 12150931
1998 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. Molecular endocrinology (Baltimore, Md.) 240 9514159
2000 Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nature genetics 226 10835633
2007 Expression of LHX3 and SOX2 during mouse inner ear development. Gene expression patterns : GEP 133 17604700
1995 Expression pattern of the murine LIM class homeobox gene Lhx3 in subsets of neural and neuroendocrine tissues. Developmental dynamics : an official publication of the American Association of Anatomists 133 7626792
2005 PITX genes are required for cell survival and Lhx3 activation. Molecular endocrinology (Baltimore, Md.) 108 15761027
2001 Early embryonic expression of a LIM-homeobox gene Cs-lhx3 is downstream of beta-catenin and responsible for the endoderm differentiation in Ciona savignyi embryos. Development (Cambridge, England) 88 11566860
2004 Regulation of the follicle-stimulating hormone beta gene by the LHX3 LIM-homeodomain transcription factor. Endocrinology 80 15271874
2015 miR-218 is essential to establish motor neuron fate as a downstream effector of Isl1-Lhx3. Nature communications 76 26212498
2007 Four novel mutations of the LHX3 gene cause combined pituitary hormone deficiencies with or without limited neck rotation. The Journal of clinical endocrinology and metabolism 71 17327381
2006 Clinical case seminar: a novel LHX3 mutation presenting as combined pituitary hormonal deficiency. The Journal of clinical endocrinology and metabolism 67 16394081
2012 Fusion protein Isl1-Lhx3 specifies motor neuron fate by inducing motor neuron genes and concomitantly suppressing the interneuron programs. Proceedings of the National Academy of Sciences of the United States of America 65 22343290
2008 Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss. Human molecular genetics 65 18407919
1999 Differential activation of pituitary hormone genes by human Lhx3 isoforms with distinct DNA binding properties. Molecular endocrinology (Baltimore, Md.) 65 10598593
2007 Lhx3, a LIM domain transcription factor, is regulated by Pou4f3 in the auditory but not in the vestibular system. The European journal of neuroscience 58 17331196
2001 LHX3 transcription factor mutations associated with combined pituitary hormone deficiency impair the activation of pituitary target genes. Gene 56 11255008
2007 Mechanisms underlying pituitary hypoplasia and failed cell specification in Lhx3-deficient mice. Developmental biology 50 18037398
2001 An isoform-specific inhibitory domain regulates the LHX3 LIM homeodomain factor holoprotein and the production of a functional alternate translation form. The Journal of biological chemistry 49 11470784
2009 Spatio-temporal intersection of Lhx3 and Tbx6 defines the cardiac field through synergistic activation of Mesp. Developmental biology 47 19389354
2006 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. Molecular endocrinology (Baltimore, Md.) 43 16613990
2017 Hypothalamic sonic hedgehog is required for cell specification and proliferation of LHX3/LHX4 pituitary embryonic precursors. Development (Cambridge, England) 42 28807898
2004 Pathophysiology of syndromic combined pituitary hormone deficiency due to a LHX3 defect in light of LHX3 and LHX4 expression during early human development. Gene expression patterns : GEP 40 15567726
2001 Role of the LIM domains in DNA recognition by the Lhx3 neuroendocrine transcription factor. Gene 40 11602361
2000 Molecular analysis of LHX3 and PROP-1 in pituitary hormone deficiency patients with posterior pituitary ectopia. The Journal of clinical endocrinology and metabolism 40 10946868
2013 A human FSHB promoter SNP associated with low FSH levels in men impairs LHX3 binding and basal FSHB transcription. Endocrinology 39 23766128
2006 Reduced expression of the LIM-homeobox gene Lhx3 impairs growth and differentiation of Rathke's pouch and increases cell apoptosis during mouse pituitary development. Mechanisms of development 36 16859901
2011 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. European journal of pediatrics 34 21249393
2003 Clinical characteristics and molecular analysis of PIT1, PROP1,LHX3, and HESX1 in combined pituitary hormone deficiency patients with abnormal pituitary MR imaging. Hormone research 34 14646405
1999 Characterization of the porcine Lhx3/LIM-3/P-Lim LIM homeodomain transcription factor. Molecular and cellular endocrinology 33 10195693
2010 PROP1, HESX1, POU1F1, LHX3 and LHX4 mutation and deletion screening and GH1 P89L and IVS3+1/+2 mutation screening in a Dutch nationwide cohort of patients with combined pituitary hormone deficiency. Hormone research in paediatrics 32 20389107
2007 Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency. Arquivos brasileiros de endocrinologia e metabologia 32 18157385
1995 Genomic structure and chromosomal localization of the mouse LIM/homeobox gene Lhx3. Genomics 32 7665181
2001 A point mutation in the LIM domain of Lhx3 reduces activation of the glycoprotein hormone alpha-subunit promoter. The Journal of biological chemistry 31 11279219
2000 The homeodomain coordinates nuclear entry of the Lhx3 neuroendocrine transcription factor and association with the nuclear matrix. The Journal of biological chemistry 28 10818088
2000 Analysis of the human LHX3 neuroendocrine transcription factor gene and mapping to the subtelomeric region of chromosome 9. Gene 27 10717474
2009 Evolutionary origins of blastoporal expression and organizer activity of the vertebrate gastrula organizer gene lhx1 and its ancient metazoan paralog lhx3. Development (Cambridge, England) 26 19439497
2017 The Isl1-Lhx3 Complex Promotes Motor Neuron Specification by Activating Transcriptional Pathways that Enhance Its Own Expression and Formation. eNeuro 22 28451636
2014 Molecular analysis of PROP1, POU1F1, LHX3, and HESX1 in Turkish patients with combined pituitary hormone deficiency: a multicenter study. Endocrine 22 25500790
2011 A contracted DNA repeat in LHX3 intron 5 is associated with aberrant splicing and pituitary dwarfism in German shepherd dogs. PloS one 21 22132174
2012 Symptomatic heterozygotes and prenatal diagnoses in a nonconsanguineous family with syndromic combined pituitary hormone deficiency resulting from two novel LHX3 mutations. The Journal of clinical endocrinology and metabolism 19 22238406
2014 Lhx3 and Lhx4 suppress Kolmer-Agduhr interneuron characteristics within zebrafish axial motoneurons. Development (Cambridge, England) 18 25231761
2018 Heterozygous LHX3 mutations may lead to a mild phenotype of combined pituitary hormone deficiency. European journal of human genetics : EJHG 17 30262920
2010 Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo. Proceedings of the National Academy of Sciences of the United States of America 17 21149718
2005 Two promoters mediate transcription from the human LHX3 gene: involvement of nuclear factor I and specificity protein 1. Endocrinology 17 16179410
2012 A recessive mutation resulting in a disabling amino acid substitution (T194R) in the LHX3 homeodomain causes combined pituitary hormone deficiency. Hormone research in paediatrics 16 22286346
2007 Mutations in the LHX3 gene cause dysregulation of pituitary and neural target genes that reflect patient phenotypes. Gene 16 17616267
2001 Expression screening for Lhx3 downstream genes identifies Thg-1pit as a novel mouse gene involved in pituitary development. Gene 15 11707329
1998 The LIM homeobox protein mLIM3/Lhx3 induces expression of the prolactin gene by a Pit-1/GHF-1-independent pathway in corticotroph AtT20 cells. FEBS letters 15 9714537
2008 Crystallization of an Lhx3-Isl1 complex. Acta crystallographica. Section F, Structural biology and crystallization communications 14 18391431
2017 Two novel LHX3 mutations in patients with combined pituitary hormone deficiency including cervical rigidity and sensorineural hearing loss. BMC endocrine disorders 13 28302169
2014 Pituitary dwarfism in Saarloos and Czechoslovakian wolfdogs is associated with a mutation in LHX3. Journal of veterinary internal medicine 13 25273400
2011 A distal modular enhancer complex acts to control pituitary- and nervous system-specific expression of the LHX3 regulatory gene. Molecular endocrinology (Baltimore, Md.) 11 22194342
2009 LHX3 and LHX4 transcription factors in pituitary development and disease. Pediatric endocrinology reviews : PER 11 19337183
2001 Identification of porcine Lhx3 and SF1 as candidate genes for QTL affecting growth and reproduction traits in swine. Animal genetics 11 11736804
2013 Cell-specific actions of a human LHX3 gene enhancer during pituitary and spinal cord development. Molecular endocrinology (Baltimore, Md.) 10 24100213
2010 A naturally occurring polymorphism at Drosophila melanogaster Lim3 Locus, a homolog of human LHX3/4, affects Lim3 transcription and fly lifespan. PloS one 10 20838645
2005 Serine/threonine/tyrosine phosphorylation of the LHX3 LIM-homeodomain transcription factor. Journal of cellular biochemistry 10 15517599
2017 Zinc finger gene nolz1 regulates the formation of retinal progenitor cells and suppresses the Lim3/Lhx3 phenotype of retinal bipolar cells in chicken retina. Developmental dynamics : an official publication of the American Association of Anatomists 8 29139167
2013 LHX3 interacts with inhibitor of histone acetyltransferase complex subunits LANP and TAF-1β to modulate pituitary gene regulation. PloS one 8 23861948
2012 Solution structure of the LIM-homeodomain transcription factor complex Lhx3/Ldb1 and the effects of a pituitary mutation on key Lhx3 interactions. PloS one 8 22848397
2010 Spatial and temporal expression of two transcriptional isoforms of Lhx3, a LIM class homeobox gene, during embryogenesis of two phylogenetically remote ascidians, Halocynthia roretzi and Ciona intestinalis. Gene expression patterns : GEP 8 20123132
2009 Regulation of porcine pituitary glycoprotein hormone alpha subunit gene with LIM-homeobox transcription factor Lhx3. The Journal of reproduction and development 8 19444006
2007 Transgenic mice expressing LHX3 transcription factor isoforms in the pituitary: effects on the gonadotrope axis and sex-specific reproductive disease. Journal of cellular physiology 8 17311285
2014 Lhx3 is required to maintain cancer cell development of high-grade oligodendroglioma. Molecular and cellular biochemistry 7 25399296
2017 Interactions between LHX3- and ISL1-family LIM-homeodomain transcription factors are conserved in Caenorhabditis elegans. Scientific reports 6 28676648
2015 Atlanto-axial malformation and instability in dogs with pituitary dwarfism due to an LHX3 mutation. Journal of veterinary internal medicine 6 25586673
2012 Replication study of the association of SNPs in the LHX3-QSOX2 and IGF1 loci with adult height in the Japanese population; wide-ranging comparison of each SNP genotype distribution. Legal medicine (Tokyo, Japan) 6 22503243
2008 Expression and function of the LIM homeobox containing genes Lhx3 and Lhx4 in the mouse placenta. Developmental dynamics : an official publication of the American Association of Anatomists 6 18425848
2024 Lhx3/4 initiates a cardiopharyngeal-specific transcriptional program in response to widespread FGF signaling. PLoS biology 5 38271304
2021 Dwarfism in Tibetan Terrier dogs with an LHX3 mutation. Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc 5 33890524
2013 The role of DNA methylation in regulation of the murine Lhx3 gene. Gene 5 24183897
2018 Generation and characterization of Lhx3GFP reporter knockin and Lhx3loxP conditional knockout mice. Genesis (New York, N.Y. : 2000) 4 29508544
2016 Transcription of follicle-stimulating hormone subunit genes is modulated by porcine LIM homeobox transcription factors, LHX2 and LHX3. The Journal of reproduction and development 4 26853788
2024 Lhx4 surpasses its paralog Lhx3 in promoting the differentiation of spinal V2a interneurons. Cellular and molecular life sciences : CMLS 3 38970652
2020 Contrasting DNA-binding behaviour by ISL1 and LHX3 underpins differential gene targeting in neuronal cell specification. Journal of structural biology: X 3 33458649
2018 LHX3 deficiency presenting in the United States with severe developmental delay in a child of Syrian refugee parents. Endocrinology, diabetes & metabolism case reports 3 30481152
2008 Three novel single-nucleotide polymorphisms of the bovine LHX3 gene. Journal of biosciences 3 19179755
2022 Novel compound heterozygous variants in the LHX3 gene caused combined pituitary hormone deficiency: A case report. World journal of clinical cases 2 36387827
2024 Hearing impairment and vestibular function in patients with a pathogenic splice variant in the LHX3 gene. BMC medical genomics 1 39548529
2024 LHX3 promotes EMT in hepatoma cell through β-catenin/TCF4 pathway. Medical oncology (Northwood, London, England) 1 39702693
2015 Exploring genotype-phenotype relationships of the LHX3 gene on growth traits in beef cattle. Gene 1 25688878
2025 Pituitary Dwarfism and Adrenocorticotropic Hormone Deficiency in a White Swiss Shepherd Dog With LHX3 Mutation. Journal of veterinary internal medicine 0 40833232
2024 A Nonsynonymous Substitution of Lhx3 Leads to Changes in Body Size in Dogs and Mice. Genes 0 38927675

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