Affinage

LHX8

LIM/homeobox protein Lhx8 · UniProt Q68G74

Length
356 aa
Mass
39.3 kDa
Annotated
2026-06-10
63 papers in source corpus 37 papers cited in narrative 37 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

LHX8 (Lhx7/L3) is a LIM-homeodomain transcription factor that binds the TGATTG element (LBE) and acts as a master regulator of cell-fate specification across the basal forebrain, ovary, and craniofacial primordia (PMID:25949113, PMID:9598319). In the basal forebrain it is required for the differentiation of cholinergic neurons: null mice lose the nucleus basalis and cholinergic neurons across multiple subcortical regions while early specification markers are retained, placing LHX8 downstream of initial specification but upstream of cholinergic differentiation (PMID:12855770, PMID:15217369, PMID:15978004). It maintains cholinergic over GABAergic identity, with loss or knockdown converting cells toward a GABAergic fate via cross-inhibitory regulation between Isl1 and Lhx6 (PMID:16000160, PMID:22315402, PMID:16438949), and it sustains cholinergic function through a TrkA–NGF positive feedback loop that regulates acetylcholine release (PMID:24265310); together with Lhx6 it also drives a feed-forward circuit activating neuronal Shh (PMID:21658586). In the ovary LHX8 is essential for primordial follicle maintenance and oocyte survival, acting downstream of SOHLH1 and partially overlapping NOBOX pathways (PMID:16690745, PMID:18509161); it restrains primordial follicle activation by directly binding and repressing the Lin28a promoter, limiting PI3K-AKT/mTOR-driven activation (PMID:26076587), and its loss triggers autophagic oocyte death linked to failed meiotic DNA-damage repair (PMID:29329412). LHX8 cooperates with FIGLA and SOHLH1 through direct protein–protein interaction and mutual cross-regulation in early oocyte development (PMID:32086523, PMID:27716808). In craniofacial development LHX8 is required for palatogenesis and, redundantly with Lhx6, for molar mesenchyme specification (PMID:10611327, PMID:19591819); it promotes proliferation by repressing the cell-cycle inhibitor p57Kip2 (PMID:26071365) and complexes with the H3K9 methyltransferase Suv39h1 to silence odontoblast differentiation genes (PMID:33580754). LHX8 expression is controlled upstream by FGF8, WNT/β-catenin, retinoic acid, and WNK-OSR1 signaling (PMID:10611327, PMID:25190800, PMID:25239070, PMID:23383144), and is repressed by FOXO1 at its promoter (PMID:40670092). Nuclear localization is essential for LHX8 function, and heterozygous truncating LHX8 variants that abolish nuclear import cause female infertility with oocyte maturation arrest (PMID:36029299, PMID:27716808).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 Medium

    Defined the gene's molecular architecture and the upstream epithelial signal controlling its spatially restricted expression, establishing LHX8 as a LIM-homeodomain factor responsive to FGF8.

    Evidence Genomic cloning of exon-intron/domain structure, and FGF8 bead implantation in mandibular/maxillary explants with in situ hybridization

    PMID:9570771 PMID:9598319

    Open questions at the time
    • DNA-binding specificity not yet defined
    • No direct target genes identified
  2. 1999 High

    Showed LHX8 is required for palatogenesis with the defect intrinsic to palatal mesenchyme, defining its first essential developmental role.

    Evidence Targeted null mutation in mice with histological analysis of palatal fusion

    PMID:10611327

    Open questions at the time
    • Downstream transcriptional targets in palate unknown
    • Molecular basis of mesenchymal requirement unresolved
  3. 2003 High

    Placed LHX8 downstream of initial neuronal specification but upstream of cholinergic differentiation by showing loss of the nucleus basalis and cholinergic neurons with retention of early markers.

    Evidence Null mouse genetics with ChAT/VAChT/p75 immunostaining and Gbx1 in situ; antisense knockdown in tooth germ explants

    PMID:12703558 PMID:12855770

    Open questions at the time
    • Direct neuronal target genes not identified
    • Mechanism distinguishing specification from differentiation unresolved
  4. 2005 High

    Established LHX8 as the determinant of cholinergic versus GABAergic fate, with progenitor survival but failed cholinergic differentiation and a reciprocal rise in GABAergic identity upon loss.

    Evidence Independent knockout replication with LacZ lineage tracing and behavioral testing; siRNA knockdown in Neuro2a with dual-marker readout

    PMID:15217369 PMID:15978004 PMID:16000160

    Open questions at the time
    • Molecular mechanism of fate switch not yet defined
    • Direct repressed GABAergic targets unknown
  5. 2006 Medium

    Defined upstream control of LHX8 expression in two tissues — FGF8b/TGFβ3 epithelial signals in maxillary mesenchyme and SOHLH1 in oocytes — and demonstrated stage-dependent repression of GABAergic differentiation.

    Evidence Chick transplantation/bead implantation; Sohlh1 knockout expression analysis; Xenopus/mouse overexpression of x-Lhx7

    PMID:16438949 PMID:16456677 PMID:16690745

    Open questions at the time
    • Whether SOHLH1 regulates LHX8 directly not established
    • Temporal restriction mechanism in GABAergic repression unclear
  6. 2008 High

    Established LHX8 as essential for primordial follicle maintenance and oocyte gene expression, with partial overlap of the NOBOX pathway.

    Evidence Lhx8 knockout histology and Affymetrix microarray profiling compared to Nobox-/- datasets

    PMID:18509161

    Open questions at the time
    • Direct versus indirect targets not distinguished
    • DNA-binding motif still unknown at this stage
  7. 2011 High

    Identified a Lhx6/Lhx8-Shh feed-forward circuit, showing LHX8 activates a neuronal Shh enhancer that in turn maintains MGE patterning and interneuron output.

    Evidence Conditional double mutants, Shh conditional knockout, enhancer reporter assays, interneuron marker immunostaining

    PMID:21658586

    Open questions at the time
    • Direct LHX8 binding to the Shh enhancer not shown biochemically
    • Relative contributions of Lhx6 vs Lhx8 unresolved
  8. 2012 High

    Defined LHX8's DNA-binding element (TGATTG/LBE) and showed it maintains postmitotic cholinergic identity via cross-inhibition of the Isl1/Lhx6 program; correlated oocyte nuclear localization with epigenetic activation of the locus.

    Evidence CAST/EMSA/luciferase for LBE; conditional ablation with fate-switch markers; IHC, bisulfite sequencing, and H3-acetylation ChIP in oocytes

    PMID:22315402 PMID:22796561 PMID:25949113

    Open questions at the time
    • Genome-wide direct binding map lacking
    • Cofactors mediating cross-inhibition not identified
  9. 2013 Medium

    Connected LHX8 to upstream signaling kinases and to a cholinergic feedback loop, with WNK-OSR1 inducing LHX8 and LHX8 driving TrkA/NGF-dependent acetylcholine release.

    Evidence Wnk1 knockout and ectopic expression with knockdown; bidirectional LHX8 manipulation in primary septal neurons with ACh release measurement

    PMID:23383144 PMID:24265310

    Open questions at the time
    • Direct TrkA promoter binding not established
    • Link between WNK-OSR1 and LHX8 transcription not mechanistically dissected
  10. 2014 Medium

    Resolved direct transcriptional control of LHX8 by WNT/β-catenin via a LEF/TCF enhancer and integrated RA-FGF signaling into LHX8 regulation in craniofacial mesenchyme.

    Evidence Enhancer mapping, ChIP and luciferase reporter for Lhx8_enh1; chick RA/citral/FGF-8b/SU5402 manipulation with RT-PCR

    PMID:25190800 PMID:25239070

    Open questions at the time
    • Single LEF/TCF site versus broader regulatory region not fully resolved
    • Interplay of multiple upstream signals not integrated
  11. 2015 High

    Defined direct LHX8 target mechanisms: repression of Lin28a to restrain PI3K-AKT-driven follicle activation, and repression of p57Kip2 and dentinogenesis genes through direct and FOX-mediated regulation.

    Evidence Oocyte conditional knockout with Lin28a-promoter ChIP and genetic rescue; double knockout with ChIP/motif analysis/reporters; tooth reconstitution with bidirectional manipulation

    PMID:26071365 PMID:26076587 PMID:26081866

    Open questions at the time
    • Direct versus FOX-mediated p57Kip2 regulation not fully separated
    • Full target repertoire across tissues incomplete
  12. 2016 Medium

    Established that nuclear localization via an NLS is required for LHX8 function and identified FIGLA as a direct protein partner.

    Evidence NLS deletion mutagenesis and ectopic expression; co-immunoprecipitation for LHX8-FIGLA

    PMID:27716808

    Open questions at the time
    • Functional consequence of FIGLA interaction not tested
    • Reciprocal validation in oocytes lacking
  13. 2020 High

    Defined a cooperative FIGLA-LHX8-SOHLH1 regulatory module in which the factors cross-regulate, physically interact, and share downstream targets in early oocyte development.

    Evidence Multiple gene-edited null mice, global expression profiling, co-expression analysis, and co-IP for direct interaction

    PMID:32086523

    Open questions at the time
    • Stoichiometry and architecture of the complex unknown
    • Direct shared target binding sites not mapped genome-wide
  14. 2021 High

    Identified an LHX8-Suv39h1 chromatin-repressive complex that silences odontoblast differentiation genes via H3K9 methylation, providing a direct epigenetic mechanism downstream of FGF8.

    Evidence RNAscope co-expression, co-IP, ChIP for H3K9me at target promoters, and Suv39h1 knockdown in organ culture

    PMID:33580754

    Open questions at the time
    • Whether LHX8 recruits Suv39h1 to specific sites via its homeodomain not resolved
    • Generalizability to other tissues untested
  15. 2022 High

    Linked LHX8 to human Mendelian disease, showing heterozygous truncating variants abolish nuclear import and cause female infertility with oocyte maturation arrest.

    Evidence Exome sequencing burden test, minigene splicing assay, and subcellular localization in HeLa cells and mouse oocytes

    PMID:36029299

    Open questions at the time
    • Mechanism by which haploinsufficiency causes maturation arrest not fully defined
    • Genotype-phenotype range incompletely characterized
  16. 2025 Medium

    Placed LHX8 within a FOXO1-LHX8 axis governing granulosa cell proliferation, survival, and steroidogenesis, with FOXO1 directly repressing the LHX8 promoter.

    Evidence ChIP and luciferase for FOXO1 binding, bidirectional manipulation in KGN cells with proliferation/apoptosis/mitochondrial readouts and rescue

    PMID:40670092

    Open questions at the time
    • Granulosa-specific direct LHX8 targets not identified
    • In vivo relevance of FOXO1-LHX8 axis untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified, genome-wide map of direct LHX8 binding sites and tissue-specific cofactor repertoires that explains how one factor governs cholinergic, oogenic, and craniofacial programs remains unresolved.
  • No genome-wide ChIP-seq binding atlas across tissues
  • Structural basis of partner selectivity (FIGLA, SOHLH1, Suv39h1) unknown
  • Mechanism integrating multiple upstream signals into LHX8 expression incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1474165 Reproduction 3 R-HSA-4839726 Chromatin organization 1
Partners
FIGLALHX6NOBOXSOHLH1SUV39H1
Complex memberships
FIGLA-LHX8-SOHLH1 oocyte regulatory moduleLHX8-Suv39h1 H3K9 methyltransferase repressor complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Lhx7 (LHX8 alias) expression in mandibular mesenchyme is under the control of epithelium-derived signals, and bead implantation experiments demonstrated that FGF8 is primarily responsible for the restricted expression of Lhx6 and Lhx7 in the oral aspect of the maxillary and mandibular processes. Explant cultures, bead implantation experiments with FGF8 protein in vitro, whole-mount in situ hybridization Development Medium 9570771
1999 Lhx8 null mutation in mice results in failure of palatal shelf fusion (cleft secondary palate), with the primary defect intrinsic to palatal mesenchyme, establishing Lhx8 as required for palatogenesis. Targeted gene deletion (null mutation), histological analysis of mutant embryos Proceedings of the National Academy of Sciences of the United States of America High 10611327
1998 Lhx8 encodes a LIM-homeodomain protein containing two tandemly repeated LIM motifs and a homeodomain; the gene is composed of 9 exons and 8 introns, with the first LIM domain encoded by exons 2-3, the second by exon 4, and the homeodomain by exons 6-8; it is localized to the distal region of mouse chromosome 3. Genomic cloning, exon-intron structure determination, in situ chromosomal hybridization Genomics Medium 9598319
2003 Lhx8 null mutation leads to absence of the nucleus basalis and marked reduction of cholinergic neurons in multiple subcortical forebrain regions including caudate-putamen, medial septal nucleus, and nucleus of the diagonal band, while cells expressing Gbx1 (early specification marker) are preserved, placing Lhx8 downstream of initial specification but upstream of cholinergic differentiation. Null mutation mouse genetics, ChAT/VAChT/p75 immunostaining, in situ hybridization for Gbx1 and truncated Lhx8 mRNA Proceedings of the National Academy of Sciences of the United States of America High 12855770
2003 Antisense oligonucleotide knockdown of Lhx8 in tooth germ explants suppresses dental mesenchymal cell proliferation, induces apoptosis, and downregulates expression of Lhx6, Msx1, Msx2, Bmp4, and Gsc, establishing Lhx8 as required for mesenchymal cell survival and upstream of these odontogenic factors. Antisense oligodeoxynucleotide treatment of tooth germ explants, histochemistry, ultrastructural analysis, mRNA expression analysis Archives of histology and cytology Medium 12703558
2004 L3/Lhx8 gene disruption in mice leads to marked reduction of basal forebrain cholinergic neurons (choline acetyltransferase, vesicular acetylcholine transporter, and p75 NGF receptor positive), while cholinergic brainstem and spinal motor neurons and other neurotransmitter phenotypes in the basal forebrain are unaffected, demonstrating a specific role in basal forebrain cholinergic neuron development. Gene-disrupted mouse generation, immunostaining for cholinergic and other neuronal markers The European journal of neuroscience High 15217369
2005 Lhx7 (LHX8 alias) knockout mice have severe deficits in forebrain cholinergic neurons; progenitors survive (detected by LacZ reporter) but fail to generate cholinergic interneurons in the striatum and projection neurons in the basal forebrain, indicating Lhx7 is required for specification or differentiation rather than survival of progenitors. Loss is associated with spatial learning and memory deficits. Targeted allele replacement with LacZ reporter, immunohistochemistry, behavioral testing (Morris water maze, radial maze) The European journal of neuroscience High 15978004
2005 L3/Lhx8 knockdown via siRNA in Neuro2a cells decreases cholinergic marker levels while dramatically increasing GABAergic marker expression and GABAergic cell number, demonstrating that Lhx8 determines cholinergic versus GABAergic cell fate. siRNA knockdown in neuroblastoma cell line, immunostaining for cholinergic and GABAergic markers Journal of neurochemistry Medium 16000160
2006 Sohlh1 disruption causes downregulation of Lhx8 in oocytes, placing Lhx8 downstream of Sohlh1 in the transcriptional hierarchy controlling oogenesis. Sohlh1 knockout mouse genetics, gene expression analysis in mutant ovaries Proceedings of the National Academy of Sciences of the United States of America Medium 16690745
2006 In Xenopus, overexpression of x-Lhx7 inhibits GABAergic specification in Dlx-expressing forebrain areas at early but not late embryonic stages, and x-Lhx7 almost totally represses GABAergic differentiation at early stages in subpallial mouse primary neurons in culture, demonstrating a temporal role in neurotransmitter specification. In vivo overexpression in Xenopus embryos, primary neuron culture from mouse subpallium with x-Lhx7 overexpression Developmental biology Medium 16438949
2007 Lhx8 (L3/Lhx8) siRNA knockdown during retinoic acid-induced neural differentiation of murine ES cells dramatically decreases ChAT-positive cholinergic cells, and overexpression of L3/Lhx8 rescues this effect, without changes in Tuj1+ neuron or GABA+ cell numbers, establishing Lhx8 as a key factor for cholinergic differentiation of ES cells. siRNA knockdown and overexpression in murine ES cell differentiation system, immunostaining for ChAT, Tuj1, GABA Cell death and differentiation Medium 17318222
2008 Lhx8 knockout females lose oocytes within 7 days after birth; Lhx8-/- ovaries fail to maintain primordial follicles and show downregulation of oocyte-specific genes including Gdf9, Pou5f1, Nobox, Kit, and Kitl; 44% of genes downregulated >5-fold in Lhx8-/- ovaries are preferentially expressed in oocytes; comparison with Nobox-/- ovaries identified 34 commonly regulated genes, indicating partial overlap of Lhx8 and Nobox pathways. Lhx8 knockout mice, histology, Affymetrix microarray gene expression profiling, comparison with Nobox-/- datasets Biology of reproduction High 18509161
2011 Lhx6 and Lhx8 are both required in early-born MGE neurons to activate expression of a Shh enhancer, driving neuronal Shh expression. Genetic elimination of Shh in MGE mantle zone neurons reduces Lhx6, Lhx8, and Nkx2-1 expression in the rostrodorsal MGE and causes preferential reduction of late-born somatostatin+ and parvalbumin+ cortical interneurons, placing Lhx6/Lhx8 upstream of Shh in a feed-forward circuit. Conditional Lhx6/Lhx8 double mutant mice, Shh conditional knockout in MGE mantle zone, Shh enhancer reporter assays, interneuron marker immunostaining Neuron High 21658586
2009 Lhx6 and Lhx7 (LHX8 alias) double homozygous mice lack molar teeth due to failure of molar mesenchyme specification (not BA1 patterning defect) and have cranial skeletal defects and cleft palate, demonstrating that Lhx6 and Lhx7 have redundant roles in dentition and craniofacial development. Compound mutant mouse genetics (all allele combinations), histology, skeletal preparations Developmental biology High 19591819
2012 Conditional ablation of Lhx7 in postmitotic striatal cholinergic interneurons causes loss of subtype-specific markers (ChAT, Isl1) and respecification into Lhx6-expressing GABAergic interneurons, demonstrating that Lhx7 maintains cholinergic identity by gating cross-inhibitory regulation between Isl1 and Lhx6. Conditional gene ablation in mice (Cre-lox), immunostaining for cholinergic and GABAergic markers, expression analysis of Isl1 and Lhx6 Proceedings of the National Academy of Sciences of the United States of America High 22315402
2012 LHX8 protein is localized to the nucleus of oocytes, and its expression increases during primordial follicle activation; this is correlated with demethylation of the Lhx8-3' UTR and increased histone H3 acetylation at the Lhx8 locus. Immunohistochemistry, quantitative PCR, western blot, bisulfite sequencing, ChIP-QPCR for H3 acetylation Gene Medium 22796561
2012 LHX8 DNA binding element was identified as TGATTG (LBE) by CAST analysis; EMSA confirmed high-affinity binding of Lhx8 to LBE; luciferase reporter assay demonstrated that Lhx8 augments transcriptional activity through this element. CAST (Cyclic Amplification of Sequence Target) analysis, EMSA, luciferase reporter assay Development & reproduction Medium 25949113
2013 Lhx8 transcription factor regulates cholinergic function in rat septal cholinergic neurons by modulating TrkA expression in vitro and in vivo, resulting in regulated acetylcholine release. NGF regulates Lhx8 expression and function, which is potentiated by Lhx8-induced TrkA expression, establishing a positive feedback loop between Lhx8, TrkA, and NGF. Lhx8 knockdown/overexpression in primary rat septal cholinergic neurons and in vivo, TrkA expression analysis, acetylcholine release measurement The Journal of biological chemistry Medium 24265310
2013 WNK1 and WNK4 kinases induce Lhx8 expression in mammalian cells through OSR1; WNK1 knockout mice have reduced Lhx8 expression; neural specification is inhibited by knockdown of both Wnk1/Wnk4 or Lhx8, placing Lhx8 downstream of WNK-OSR1 signaling in neural development. Wnk1 knockout mice, ectopic expression in mammalian cells, siRNA knockdown, RT-PCR PloS one Medium 23383144
2014 WNT/β-catenin signaling directly regulates Lhx8 expression in maxillary arch cells through an enhancer (Lhx8_enh1) located upstream of Lhx8 that contains an evolutionarily conserved LEF/TCF binding site; WNT/β-catenin signaling is essential for Lhx8 expression in these cells and Lhx8_enh1 is a direct target of this pathway. ChIP for histone enhancer marks, genome-wide enhancer mapping, luciferase reporter assays with Lhx8_enh1, in vitro WNT pathway manipulation in maxillary arch cells The Journal of biological chemistry Medium 25190800
2014 Retinoic acid (RA) signaling downregulates Lhx8 expression in maxillary mesenchyme; this downregulation is rescued by FGF-8b treatment, indicating Lhx8 is downstream of RA signaling through FGF signals in upper jaw development. Exogenous RA application and citral treatment in chick embryo, FGF-8b bead implantation, SU5402 pan-FGF antagonist treatment, RT-PCR Journal of bioscience and bioengineering Medium 25239070
2015 Lhx8 regulates dental mesenchyme differentiation via Wnt and TGFβ pathways; Lhx8 knockdown accelerates dental mesenchyme differentiation while overexpression attenuates dentin formation; Lhx8 transcriptionally activates Wnt and TGFβ pathways and its attenuation upregulates multiple dentinogenesis genes (Dspp, Col1a1, osteocalcin). Dental epithelium-mesenchyme reconstitution in E16.5 tooth organ, Lhx8 knockdown and overexpression, gene profiling, in vivo transplantation of human dental pulp stem cells Biomaterials Medium 26081866
2015 Conditional Lhx8 deficiency in oocytes of primordial follicles causes massive primordial oocyte activation; LHX8 represses Lin28a expression by binding to the Lin28a promoter; depletion of Lin28a in Lhx8-deficient oocytes partially suppresses primordial oocyte activation, establishing an LHX8-LIN28A pathway that controls primordial follicle activation indirectly through the PI3K-AKT/mTOR pathway. Oocyte-specific conditional Lhx8 knockout, ChIP for LHX8 binding to Lin28a promoter, Lin28a knockdown in Lhx8-deficient oocytes, FOXO3 nucleocytoplasmic translocation assay, rpS6 activation analysis BMC biology High 26076587
2015 LHX6 and LHX8 negatively regulate p57Kip2 (Cdkn1c) expression in the prospective palate; loss of both Lhx6 and Lhx8 leads to upregulation of p57Kip2 and impaired cell proliferation; ChIP, in silico motif analysis, and reporter assays showed LHX6/LHX8 regulate p57Kip2 via both direct binding and indirect mechanisms mediated by Forkhead box (FOX) family transcription factors. Lhx6;Lhx8 double knockout mice, genome-wide transcriptional profiling, chromatin immunoprecipitation, in silico motif analysis, in vitro reporter assays Human molecular genetics High 26071365
2016 Bovine LHX8 contains a nuclear localization signal required for nuclear import; LHX8 is predominantly localized in the nucleus when ectopically expressed in mammalian cells; a novel protein-protein interaction between LHX8 and FIGLA was detected. Nuclear localization signal deletion mutagenesis, ectopic expression in mammalian cells, co-immunoprecipitation PloS one Medium 27716808
2017 Rainbow trout Lhx8a and Lhx8b interact with a novel germ cell-specific nuclear protein Borealin-2 (containing an Nbl1 domain); this interaction was confirmed by yeast two-hybrid screening and bimolecular fluorescence complementation (BiFC) assay. Yeast two-hybrid screening, bimolecular fluorescence complementation (BiFC) assay, GFP reporter localization PloS one Medium 28151980
2018 Lhx8-/- oocytes show normal numbers during embryonic development; rapid oocyte loss begins before birth and is caused by activation of autophagy (not apoptosis), associated with failure to repair meiotic DNA damage; DNA damage repair genes are downregulated throughout the short lifespan of Lhx8-/- oocytes. Lhx8 knockout histology at serial timepoints, autophagy marker analysis, DNA damage markers, gene expression analysis Biology of reproduction Medium 29329412
2020 FIGLA, LHX8, and SOHLH1 are co-expressed in the same germ cell subsets; FIGLA ablation dramatically reduces LHX8, NOBOX, SOHLH1, and SOHLH2 protein abundance; FIGLA, LHX8, and SOHLH1 cross-regulate each other and cooperate by direct protein-protein interaction, sharing downstream gene targets in early oocyte development. Gene-edited null mice for Figla, Lhx8, and Sohlh1, global gene expression profiling, co-expression analysis, co-immunoprecipitation for protein-protein interaction Nucleic acids research High 32086523
2021 Lhx8 forms a complex with Suv39h1 (a histone-lysine N-methyltransferase) in dental mesenchyme; the Lhx8/Suv39h1 complex represses odontoblast differentiation-related genes by methylating H3K9 on their promoters; FGF8 activates Lhx8 expression while BMP2 represses it; Suv39h1 knockdown blocks Lhx8 and FGF8 function. RNAscope co-expression assay, ex vivo organ culture with Suv39h1 knockdown, FGF8/BMP2 treatment, ChIP for H3K9 methylation at target gene promoters, co-immunoprecipitation for Lhx8-Suv39h1 interaction Journal of cellular and molecular medicine High 33580754
2022 Heterozygous loss-of-function LHX8 variants (truncating mutations) cause female infertility with oocyte maturation arrest; all identified variants produce truncated LHX8 protein and result in loss of LHX8 nuclear localization in both HeLa cells and mouse oocytes, demonstrating that nuclear localization is essential for LHX8 function. Exome sequencing with gene-based burden test, minigene splicing assay, expression in HeLa cells, subcellular localization in HeLa cells and mouse oocytes Genetics in medicine High 36029299
2022 WNK1 HSN2 splice variant promotes neurite outgrowth through OSR1 activation and GSK3β, which together induce LHX8 expression; HSN2 mutants found in hereditary sensory and autonomic neuropathy type II patients suppress SPAK/OSR1 activation and LHX8 induction, and inhibit neurite outgrowth by preventing interaction of HSN2 with GSK3β. Overexpression and knockdown of HSN2/WNK1, OSR1, and GSK3β in cells; neurite outgrowth assays; co-immunoprecipitation for HSN2-GSK3β interaction; LHX8 expression analysis Scientific reports Medium 36151370
2023 LNC1845, a divergent lncRNA, acts as a cis-regulator of LHX8 expression in human germ cells by modulating histone modifications H3K4me3 and H3K27Ac at the LHX8 locus during in vitro differentiation of human pluripotent stem cells to germ cells. In vitro differentiation of human pluripotent stem cells, lncRNA knockdown/functional dissection, ChIP for H3K4me3 and H3K27Ac eLife Medium 36602025
2025 FOXO1 binds to the LHX8 promoter and reduces its transcriptional activity; FOXO1 knockdown or LHX8 overexpression promotes granulosa cell proliferation, inhibits apoptosis, and increases mitochondrial ATP, mtDNA, estradiol, and aromatase; LHX8 overexpression rescues FOXO1-induced granulosa cell damage, establishing a FOXO1-LHX8 axis in granulosa cell function. ChIP for FOXO1 binding to LHX8 promoter, luciferase reporter assay for promoter activity, siRNA knockdown and overexpression in KGN cells, flow cytometry for apoptosis, CCK-8 proliferation assay The Tohoku journal of experimental medicine Medium 40670092
2021 Lhx8 promotes early proliferation of bone marrow mesenchymal stem cells (BMSCs) but inhibits subsequent osteogenic differentiation; temporal optogenetic activation of Lhx8 in the early stage of BMSC differentiation increases cell proliferation and enhances in vivo bone regeneration in a calvarial defect model. Optogenetic expression system, alkaline phosphatase/alizarin red staining, critical calvarial defect in vivo model, micro-CT and histology Stem cell research & therapy Low 34112263
2021 LHX6 and LHX8 in pharyngeal arch 1 positively regulate candidate target genes including Eya1, Barx1, Rspo2, Rspo3, and Wnt11; LHX6 ChIP confirmed binding to putative enhancers near these genes; their expression is reduced in Lhx6;Lhx8 double mutants. RNA in situ hybridization in Lhx6;Lhx8 mutants, ChIP for LHX6 binding to enhancers near candidate target genes Gene expression patterns Medium 34861428
2022 In Japanese flounder, PoLhx8a directly interacts with PoFigla and PoNobox as confirmed by yeast two-hybrid, BiFC, and co-immunoprecipitation experiments. Yeast two-hybrid, bimolecular fluorescence complementation (BiFC), co-immunoprecipitation Gene Medium 35063574
2006 L3/Lhx8 expression in the chick maxillary mesenchyme requires signals from overlying oral epithelium; transplantation experiments showed that Fgf-8b and TGF-β3 beads can induce Lhx8 expression in epithelium-free mesenchymal grafts. Maxillary process transplantation into limb bud (with/without epithelium), bead implantation with FGF-8b or TGF-β3, in situ hybridization Anatomy and embryology Medium 16456677

Source papers

Stage 0 corpus · 63 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Expression and regulation of Lhx6 and Lhx7, a novel subfamily of LIM homeodomain encoding genes, suggests a role in mammalian head development. Development (Cambridge, England) 261 9570771
2006 Oogenesis requires germ cell-specific transcriptional regulators Sohlh1 and Lhx8. Proceedings of the National Academy of Sciences of the United States of America 217 16690745
2003 The LIM-homeobox gene Lhx8 is required for the development of many cholinergic neurons in the mouse forebrain. Proceedings of the National Academy of Sciences of the United States of America 184 12855770
2011 Lhx6 and Lhx8 coordinately induce neuronal expression of Shh that controls the generation of interneuron progenitors. Neuron 127 21658586
1999 Isolated cleft palate in mice with a targeted mutation of the LIM homeobox gene lhx8. Proceedings of the National Academy of Sciences of the United States of America 123 10611327
2008 Lim homeobox gene, lhx8, is essential for mouse oocyte differentiation and survival. Biology of reproduction 122 18509161
2020 FIGLA, LHX8 and SOHLH1 transcription factor networks regulate mouse oocyte growth and differentiation. Nucleic acids research 85 32086523
2004 The LIM homeobox gene, L3/Lhx8, is necessary for proper development of basal forebrain cholinergic neurons. The European journal of neuroscience 79 15217369
2005 Loss of forebrain cholinergic neurons and impairment in spatial learning and memory in LHX7-deficient mice. The European journal of neuroscience 75 15978004
2015 Lhx8 regulates primordial follicle activation and postnatal folliculogenesis. BMC biology 71 26076587
2009 The LIM homeodomain transcription factors Lhx6 and Lhx7 are key regulators of mammalian dentition. Developmental biology 54 19591819
2005 L3/Lhx8 is involved in the determination of cholinergic or GABAergic cell fate. Journal of neurochemistry 53 16000160
2015 Lhx8 mediated Wnt and TGFβ pathways in tooth development and regeneration. Biomaterials 48 26081866
2017 Zearalenone exposure impairs ovarian primordial follicle formation via down-regulation of Lhx8 expression in vitro. Toxicology and applied pharmacology 45 28089945
2002 The homeobox genes Lhx7 and Gbx1 are expressed in the basal forebrain cholinergic system. Neuroscience 44 11801365
2015 Lhx6 and Lhx8: cell fate regulators and beyond. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 41 26148970
2006 GABAergic specification in the basal forebrain is controlled by the LIM-hd factor Lhx7. Developmental biology 41 16438949
2004 Cloning and developmental expression patterns of Dlx2, Lhx7 and Lhx9 in the medaka fish (Oryzias latipes). Mechanisms of development 41 15210202
2012 Transcription factor LIM homeobox 7 (Lhx7) maintains subtype identity of cholinergic interneurons in the mammalian striatum. Proceedings of the National Academy of Sciences of the United States of America 38 22315402
2007 L3/Lhx8 is a pivotal factor for cholinergic differentiation of murine embryonic stem cells. Cell death and differentiation 33 17318222
2021 Performance of DNA methylation analysis of ASCL1, LHX8, ST6GALNAC5, GHSR, ZIC1 and SST for the triage of HPV-positive women: Results from a Dutch primary HPV-based screening cohort. International journal of cancer 32 34558659
2007 Analysis of LHX8 mutation in premature ovarian failure. Fertility and sterility 29 17624344
1998 Structure and chromosomal localization of a murine LIM/homeobox gene, Lhx8. Genomics 25 9598319
2018 Lhx8 ablation leads to massive autophagy of mouse oocytes associated with DNA damage. Biology of reproduction 24 29329412
2003 Expression and role of Lhx8 in murine tooth development. Archives of histology and cytology 24 12703558
2015 Lhx6 and Lhx8 promote palate development through negative regulation of a cell cycle inhibitor gene, p57Kip2. Human molecular genetics 23 26071365
2013 WNK signaling is involved in neural development via Lhx8/Awh expression. PloS one 23 23383144
2012 Expression and epigenetic dynamics of transcription regulator Lhx8 during mouse oogenesis. Gene 23 22796561
2013 LIM homeobox 8 (Lhx8) is a key regulator of the cholinergic neuronal function via a tropomyosin receptor kinase A (TrkA)-mediated positive feedback loop. The Journal of biological chemistry 21 24265310
2002 Comparison of the expression patterns of two LIM-homeodomain genes, Lhx6 and L3/Lhx8, in the developing palate. Orthodontics & craniofacial research 19 12086327
2023 Evaluation of DNA methylation biomarkers ASCL1 and LHX8 on HPV-positive self-collected samples from primary HPV-based screening. British journal of cancer 16 37100874
2022 Heterozygous loss-of-function variants in LHX8 cause female infertility characterized by oocyte maturation arrest. Genetics in medicine : official journal of the American College of Medical Genetics 16 36029299
2021 Temporal induction of Lhx8 by optogenetic control system for efficient bone regeneration. Stem cell research & therapy 13 34112263
2020 GAS5 which is regulated by Lhx8 promotes the recovery of learning and memory in rats with cholinergic nerve injury. Life sciences 13 32890602
2012 Evaluation of the LIM homeobox genes LHX6 and LHX8 as candidates for Tourette syndrome. Genes, brain, and behavior 13 22435649
2014 Identification of a face enhancer reveals direct regulation of LIM homeobox 8 (Lhx8) by wingless-int (WNT)/β-catenin signaling. The Journal of biological chemistry 12 25190800
2014 Retinoic acid regulates Lhx8 expression via FGF-8b to the upper jaw development of chick embryo. Journal of bioscience and bioengineering 12 25239070
2012 Lhx8 promote differentiation of hippocampal neural stem/progenitor cells into cholinergic neurons in vitro. In vitro cellular & developmental biology. Animal 11 23150137
2010 Comparative study of LHX8 expression between odontoma and dental tissue-derived stem cells. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 11 21143530
2007 Knockdown of the L3/Lhx8 gene suppresses cholinergic differentiation of murine embryonic stem cell-derived spheres. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 11 18248940
2005 Sexually dimorphic effects of the Lhx7 null mutation on forebrain cholinergic function. Neuroscience 11 16338089
2023 Validation of ASCL1 and LHX8 Methylation Analysis as Primary Cervical Cancer Screening Strategy in South African Women with Human Immunodeficiency Virus. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 9 36366827
2022 WNK1/HSN2 mediates neurite outgrowth and differentiation via a OSR1/GSK3β-LHX8 pathway. Scientific reports 9 36151370
2016 Bovine Lhx8, a Germ Cell-Specific Nuclear Factor, Interacts with Figla. PloS one 9 27716808
2012 Identification and Characterization of LHX8 DNA Binding Elements. Development & reproduction 9 25949113
2006 Expression and regulation of the LIM homeodomain gene L3/Lhx8 suggests a role in upper lip development of the chick embryo. Anatomy and embryology 9 16456677
2021 FGF8 and BMP2 mediated dynamic regulation of dental mesenchyme proliferation and differentiation via Lhx8/Suv39h1 complex. Journal of cellular and molecular medicine 7 33580754
2017 Lhx8 interacts with a novel germ cell-specific nuclear factor containing an Nbl1 domain in rainbow trout (Oncorhynchus mykiss). PloS one 7 28151980
2014 Overexpression of Lhx8 inhibits cell proliferation and induces cell cycle arrest in PC12 cell line. In vitro cellular & developmental biology. Animal 7 25475040
2013 Upregulation of Lhx8 increase VAChT expression and ACh release in neuronal cell line SHSY5Y. Neuroscience letters 7 24316404
2023 Single-cell profiling of lncRNAs in human germ cells and molecular analysis reveals transcriptional regulation of LNC1845 on LHX8. eLife 6 36602025
2022 Functional differentiation of two lhx8 paralogs and possible regulatory role of lhx8a in Japanese flounder (Paralichthys olivaceus). Gene 5 35063574
2008 Sex differences in water maze performance and cortical neurotrophin levels of LHX7 null mutant mice. Neuroscience 4 19095044
2025 Modulation of the tumor microenvironment through BMAL1-LHX8 axis augments the sensitivity of ameloblastoma to vemurafenib. Journal of advanced research 3 41349606
2022 Posttreatment monitoring by ASCL1/LHX8 methylation analysis in women with HIV treated for cervical intraepithelial neoplasia grade 2/3. AIDS (London, England) 3 35152224
2021 Candidate positive targets of LHX6 and LHX8 transcription factors in the developing upper jaw. Gene expression patterns : GEP 3 34861428
2023 Sohlh1 and Lhx8 are prominent biomarkers to estimate the primordial follicle pool in mice. Reproductive biology and endocrinology : RB&E 2 37194006
2026 Clinical performance of ASCL1/LHX8 DNA methylation on first-void urine to screen for cervical cancer. Communications medicine 1 41820501
2023 Mir-142-5p inhibits the osteogenic differentiation of bone marrow mesenchymal stem cells by targeting Lhx8. Heliyon 1 37809754
2026 Novel LHX8 variants associated with distinctive oocyte morphological abnormalities and maturation arrest in primary infertility. Journal of ovarian research 0 41566502
2025 FOXO1 Targets LHX8 to Promote Granulosa Cell Apoptosis. The Tohoku journal of experimental medicine 0 40670092
2017 Regulation and/or Repression of Cholinergic Differentiation of Murine Embryonic Stem Cells Using RNAi Directed Against Transcription Factor L3/Lhx8. Methods in molecular biology (Clifton, N.J.) 0 28674804
2010 Regulation and/or repression of cholinergic differentiation of murine embryonic stem cells using RNAi directed against transcription factor L3/Lhx8. Methods in molecular biology (Clifton, N.J.) 0 20686946

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