UniProtKB entry O60663 (LMX1B_HUMAN), LIM homeobox transcription factor 1-beta
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UniProt describes LMX1B as a transcription factor that regulates podocyte-expressed genes and specifies dorsal limb fate.
"Transcription factor involved in the regulation of podocyte-...specification of dorsal limb fate at both the zeugopodal and autopodal"
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UniProt records nuclear localization and three alternatively spliced human LMX1B isoforms.
"SUBCELLULAR LOCATION: Nucleus...Event=Alternative splicing; Named isoforms=3;"
Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Gene Ontology annotation of human sequence-specific DNA binding transcription factors (DbTFs) based on the TFClass database
Electronic Gene Ontology annotations created by ARBA machine learning models
LMX1B transactivation and expression in nail-patella syndrome.
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LDB1 reduces LMX1B-mediated reporter transactivation, whereas E47/shPan1 has a synergistic effect.
"While co--transfections of E47/shPan1...with LMX1B result in a synergistic effect on reporter activity, LDB1...down-regulated LMX1B-mediated transactivation irrespective of E47/shPan1."
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Human homeodomain mutations abolish LMX1B transactivation, while LIM-B and truncating mutations retain residual activity.
"N-terminal arm of the homeodomain abolished transactivation, while LIM B and...truncation mutations retained residual activity."
Confirmation of CLIM2/LMX1B interaction by yeast two-hybrid screening and analysis of its involvement in nail-patella syndrome.
An atlas of combinatorial transcriptional regulation in mouse and man.
Differentiation of human epidermal neural crest stem cells (hEPI-NCSC) into virtually homogenous populations of dopaminergic neurons.
Wnt signaling in midbrain dopaminergic neuron development and regenerative medicine for Parkinson's disease.
Impact of cytosine methylation on DNA binding specificities of human transcription factors.
A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape.
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
Multimodal cell maps as a foundation for structural and functional genomics.
Transcriptional induction of slit diaphragm genes by Lmx1b is required in podocyte differentiation.
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LMX1B binds candidate regulatory sequences associated with CD2AP and NPHS2 and activates reporters containing them.
"We identified several LMX1B binding sites in the putative regulatory regions of both CD2AP and NPHS2 (podocin) and demonstrated that LMX1B binds to these sequences in vitro and can activate transcription through them in cotransfection assays."
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The authors conclude that LMX1B regulates a podocyte gene program important for differentiation and function.
"Thus, LMX1B regulates the expression of multiple podocyte genes critical for podocyte differentiation and function."
Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome.
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LMX1B binds an intron-1 COL4A4 enhancer shared by mouse and human sequences and activates enhancer-containing reporters.
"LMX1B binds specifically to a putative enhancer sequence in intron 1 of both...mouse and human COL4A4 and upregulates reporter constructs containing this...enhancer-like sequence."
In vivo expression of putative LMX1B targets in nail-patella syndrome kidneys.
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Seven severely affected human NPS kidneys retained normal expression of COL4A3/COL4A4, podocin, and CD2AP.
"The expression of the alpha3 and alpha4 chains of type IV...collagen, and of podocin and CD2AP, was found to be normal in the seven...patients."
Lmx1b is essential for the development of serotonergic neurons.
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Mouse Lmx1b is required for development of central serotonergic neurons and links early Nkx2-2 specification to Pet1-dependent terminal differentiation.
"A major determinant in the cascades is an LIM homeodomain-containing gene, Lmx1b, which is required for the development of all 5-HT neurons in the central nervous system. Our results suggest that, during development of 5-HT neurons, Lmx1b is a critical intermediate factor that couples Nkx2-2-mediated early specification with Pet1-mediated terminal differentiation."
The LIM-homeodomain transcription factor LMX1B regulates expression of NF-kappa B target genes.
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In human cells, LMX1B occupies the proximal IL6 and IL8 promoters and cooperates with nuclear NF-kappaB p50/p65.
"LMX1B binds to the proximal promoter of IL-6 and IL-8 in vivo, in the vicinity...of the characterized kappaB site"
The transcriptional regulation of podocin (NPHS2) by Lmx1b and a promoter single nucleotide polymorphism.
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LMX1B binds an NPHS2 FLAT-F element and enhances promoter-reporter activity.
"Our data shows that the transcription of podocin is mainly regulated by the transcription factor Lmx1b, which binds to a FLAT-F element and displays enhancer function."
LMX1B is part of a transcriptional complex with PSPC1 and PSF.
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Mouse LMX1B co-immunoprecipitates with the transcription-associated protein PSF in MN9D cells and developing midbrain.
"Importantly, HIS and LMX1B IP experiments on MN9D cell lysates showed a clear interaction with PSF (FIG. 4B,C)."
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The study did not demonstrate direct LMX1B-NURR1 binding.
"Altogether, despite the identified interactions of LMX1B with PSF, and PSF with NURR1, we were not able to confirm direct binding of LMX1B with NURR1."
LMX1B is essential for the maintenance of differentiated podocytes in adult kidneys.
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Acute loss of Lmx1b in adult mouse podocytes dysregulates actin cytoskeleton organization.
"Cell biological and biophysical experiments with primary podocytes isolated after 1 week of Lmx1b inactivation indicated dysregulation of actin cytoskeleton organization"
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Human-podocyte ChIP and gel-shift assays show that LMX1B recognizes AT-rich FLAT elements in the ABRA and ARL4C promoters.
"Chromatin immunoprecipitation experiments in conditionally immortalized human podocytes and gel shift assays showed that LMX1B recognizes AT-rich binding sites (FLAT elements) in the promoter regions of ABRA and ARL4C"
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Adult conditional-knockout evidence casts doubt on NPHS2 as a universal direct LMX1B target.
"Together with the facts that LMX1B failed to activate an NPHS2 promoter fragment in reporter assays and that the endogenous NPHS2 gene was not upregulated in stably transfected HeLa cells inducibly producing LMX1B, 13 this finding at least casts doubt on the hypothesis that NPHS2 is a target gene of LMX1B."
LMX1B mutation with residual transcriptional activity as a cause of isolated glomerulopathy.
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The kidney-limited R246Q variant retains partial transcriptional activity and showed no dominant-negative effect in this assay.
"partial but significant impairment of R246Q transcriptional...activity. However, no dominant-negative effect of R246Q was detected"
Dysregulation of WTI (-KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation.
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In human podocyte overexpression models, R246Q produced lower NPHS1, TRPC6, and GLEPP1 expression than wild-type LMX1B.
"However, the expression of NPHS1, TRPC6 and GLEPP1 was significantly reduced in myc-LMX1BR246Q-expressing podocytes compared to myc-LMX1BWT-expressing podocytes, suggesting that the mutation may exert a haploinsufficiency effect on the transcriptional regulation of these genes."
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R246Q reduced WT1 expression in the same model, leading the authors to propose a target-specific dominant-negative effect.
"suggesting a dominant negative effect of the mutation on the regulation of WT1 gene expression."
ATG8-dependent LMX1B-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience.
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Endogenous human LMX1B occupies regulatory regions of multiple core autophagy and selective-autophagy genes.
"Using an arbitrary twofold cut-off for targets of interest, promoter occupancy was confirmed for several core autophagy genes, including ULK1, ATG3, ATG16L1, UVRAG, as well as the autolysosomal transcription factor TFEB and the receptors and/or mitophagy genes, NDP52, OPTN, and PINK1 (Fig. 1 A)."
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LMX1B promotes basal and nutrient-stress-induced autophagic flux in human cells.
"Together, these data demonstrate that LMX1B contributes to the control of autophagy gene expression in HEK293T cells, and that LMX1B depletion dampens basal/housekeeping and nutrient stress-induced autophagic flux responses."
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LMX1B controls an autophagy transcriptional program in human iPSC-derived midbrain dopaminergic neurons.
"Importantly, shRNA suppression of either LMX1A or LMX1B significantly reduced levels of ULK1, ATG2B, ATG7, ATG16L1, NDP52, OPTN, PINK1, and TFEB transcripts in mDANs, but ATG3 and p62 were not affected (Fig. 2 I)."
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A region spanning LMX1B residues 308-317 is required for robust ATG8 binding, target-gene transcription, and rotenone-stress protection.
"Δ308-317 LMX1B bound poorly to all ATG8s, failed to rescue autophagy gene expression, was unable to stimulate FLAT-promoter luciferase reporter expression, and crucially, failed to protect against rotenone in HEK293T cells and iPSC-derived human mDANs."
An Lmx1b-miR135a2 regulatory circuit modulates Wnt1/Wnt signaling and determines the size of the midbrain dopaminergic progenitor pool.
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In mouse midbrain, Lmx1b promotes dopaminergic progenitor fate while miR135a2 limits the progenitor domain.
"We show that Lmx1b promotes mDA progenitor fate, whereas miR135a2 delimits the mDA domain."
Otx2 Requires Lmx1b to Control the Development of Mesodiencephalic Dopaminergic Neurons.
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Mouse Otx2 requires Lmx1b for mesodiencephalic dopaminergic-neuron formation, with organizer-gene expression as an important mechanism.
"demonstrate that Otx2 critically depends on Lmx1b for the formation of mdDA...neurons, but not for the generation of ocular motor neurons. Moreover, our data...suggest that Lmx1b precisely maintains the expression pattern of Wnt1, Fgf8 and...En1"
Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons.
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Sustained combined Lmx1a/Lmx1b activity is required for adult mouse midbrain dopaminergic-neuron survival and mitochondrial homeostasis.
"We show here that sustained expression of Lmx1a and Lmx1b is required for the survival of adult midbrain dopaminergic neurons."