LMX1B transactivation and expression in nail-patella syndrome

Dreyer, Sandra D.; Morello, Roy; German, Michael S.; Zabel, Bernhard; Winterpacht, Andreas; Lunstrum, Gregory P.; Horton, William A.; Oberg, Kerby C.; Lee, Brendan

doi:10.1093/hmg/9.7.1067

Cited by 94 publications

(96 citation statements)

References 29 publications

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“…21 Moreover, Lmx1b and Foxc2 are critical for the Nphs2 expression. 14,19,24 Therefore, we hypothesized that the two proteins bind to the FLAT-E/ forkhead motif with a synergistic effect on Nphs2 transcription. In zebrafish, no FoxC2 homolog exists.…”

Section: Identification Of a Podocyte-specific Enhancer By Analysis Omentioning

confidence: 99%

“…16 Mutations in human LMX1B cause nail-patella syndrome, which is characterized by skeletal abnormality, nail hypoplasia, and nephropathy. 17,18 In mice, genetic ablation of Lmx1b leads to loss of Nphs2 expression 14,19 as well as loss of expression of the glomerular basement membrane (GBM) collagens Col4a3 and Col4a4, 20 suggesting that Lmx1b potentially acts as a common upstream regulator of these genes through binding to the FLAT elements. 21 Although this hypothesis is supported by an electrophoresis mobility shift assay (EMSA), conflicting results have been reported regarding the ability of a putative Lmx1b-binding enhancer to activate reporter gene expression.…”

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confidence: 99%

“…14,15 Moreover, Lmx1b is exclusively expressed in the glomerulus of the kidney, 22 as well as in other organs, including limb, eye, and brain, during development. 19,23 Thus, although Lmx1b is necessary for podocyte-specific expression of certain genes, it is not specific to podocytes, nor is it alone sufficient to direct podocyte-specific gene expression. Authors have argued that Lmx1b may interact with coactivators through its LIM domains, 19 and Ldb1 has been shown as a candidate coactivator in podocytes.…”

mentioning

confidence: 99%

“…19,23 Thus, although Lmx1b is necessary for podocyte-specific expression of certain genes, it is not specific to podocytes, nor is it alone sufficient to direct podocyte-specific gene expression. Authors have argued that Lmx1b may interact with coactivators through its LIM domains, 19 and Ldb1 has been shown as a candidate coactivator in podocytes. 22 However, its role in regulating Nphs2 expression remains to be determined.…”

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confidence: 99%

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Lmx1b and FoxC Combinatorially Regulate Podocin Expression in Podocytes

Ebarasi

Zhao

et al. 2014

Journal of the American Society of Nephrology

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Podocin is a key protein of the kidney podocyte slit diaphragm protein complex, an important part of the glomerular filtration barrier. Mutations in the human podocin gene NPHS2 cause familial or sporadic forms of renal disease owing to the disruption of filtration barrier integrity. The exclusive expression of NPHS2 in podocytes reflects its unique function and raises interesting questions about its transcriptional regulation. Here, we further define a 2.5-kb zebrafish nphs2 promoter fragment previously described and identify a 49-bp podocyte-specific transcriptional enhancer using Tol2-mediated G 0 transgenesis in zebrafish. Within this enhancer, we identified a cis-acting element composed of two adjacent DNA-binding sites (FLAT-E and forkhead) bound by transcription factors Lmx1b and FoxC. In zebrafish, double knockdown of Lmx1b and FoxC orthologs using morpholino doses that caused no or minimal phenotypic changes upon individual knockdown completely disrupted podocyte development in 40% of injected embryos. Cooverexpression of the two genes potently induced endogenous nphs2 expression in zebrafish podocytes. We found that the NPHS2 promoter also contains a cis-acting Lmx1b-FoxC motif that binds LMX1B and FoxC2. Furthermore, a genome-wide search identified several genes that carry the Lmx1b-FoxC motif in their promoter regions. Among these candidates, motif-driven podocyte enhancer activity of CCNC and MEIS2 was functionally analyzed in vivo. Our results show that podocyte expression of some genes is combinatorially regulated by two transcription factors interacting synergistically with a common enhancer. This finding provides insights into transcriptional mechanisms required for normal and pathologic podocyte functions. Normal glomerular filtration function depends on structural integrity of the filtration barrier. Glomerular podocytes play a key role in establishing and maintaining this unique filtration barrier structure. Mature podocytes are characterized by cell cycle arrest, foot process formation, and the presence of the slit diaphragm, 1 which bridges the gaps between the interdigitating foot processes of neighboring podocytes and functions as a size-selective filtration barrier. 2,3 For their differentiation, as well as for the maintenance of their complex architecture, podocytes require the expression of several specific genes in a correct spatial and temporal fashion. This notion is supported by the identification of many mutations in podocyte-expressed genes as the underlying cause of inherited renal diseases. 4 Moreover, recent studies from genetically modified mice

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Section: Identification Of a Podocyte-specific Enhancer By Analysis Omentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Lmx1b and FoxC Combinatorially Regulate Podocin Expression in Podocytes

Ebarasi

Zhao

et al. 2014

Journal of the American Society of Nephrology

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“…These proteins contain two cysteine-rich zinc-binding motifs (LIM-A and LIM-B domain) at their amino termini that are important in mediating proteinprotein interactions and a homeodomain involved in DNA binding (9,10). The LMX1B-mediated transactivation presumably requires interaction with a transcriptional complex including a helix-loop-helix protein, E47/shPan1 (11,12). During embryogenesis, Lmx1b is strongly expressed in dorsal mesenchymal tissues in mice (12).…”

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confidence: 99%

Functional Characterization of LMX1B Mutations Associated with Nail-Patella Syndrome

et al. 2005

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Nail-patella syndrome (NPS) is an autosomal dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and nephropathy. Recently, it was shown that NPS is the result of heterozygous mutations in the LIM-homeodomain gene, LMX1B. Subsequently, many mutations of the LMX1B gene have been reported in NPS patients. However, functional analyses of the mutant proteins have been performed in only a few mutations. Furthermore, the mechanisms of dominant inheritance in humans have not been established. In the present study, we analyzed the LMX1B gene in three Japanese patients with NPS and identified two novel mutations, 6 nucleotide deletion (⌬246⌵ 247Q) and V242L. These two mutations are located in the homeodomain of LMX1B.Functional analyses of the LMX1B mutants revealed that these mutants had diminished transcriptional activity and had lost DNA binding ability. Furthermore, we demonstrated that each mutant did not manifest a dominant-negative effect on the transcriptional activity of wild-type LMX1B. These results suggested that NPS is caused by loss-of-function mutations of LMX1B, and haploinsufficiency of LMX1B should be the predominant pathogenesis of NPS in humans. Nail-patella syndrome (NPS; MIM#161200) is an autosomal dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, iliac horns, and, in some cases, open-angle glaucoma and nephropathy (1-3). Nail dysplasia is the most constant feature of NPS observed at birth. The most serious aspect of NPS is nephropathy, which might develop end-stage renal failure. Although development to endstage renal failure is usually slow, a minority of cases have been reported to show rapid progression during early childhood (3,4).It has been demonstrated that mutations of the LMX1B gene, which is located on chromosome 9q34, result in NPS (5-8). LMX1B is a member of the LIM-homeodomain family of transcription factors that are involved in body-pattern formation during development (9,10). These proteins contain two cysteine-rich zinc-binding motifs (LIM-A and LIM-B domain) at their amino termini that are important in mediating proteinprotein interactions and a homeodomain involved in DNA binding (9,10). The LMX1B-mediated transactivation presumably requires interaction with a transcriptional complex including a helix-loop-helix protein, E47/shPan1 (11,12). During embryogenesis, Lmx1b is strongly expressed in dorsal mesenchymal tissues in mice (12). Lmx1bϪ/Ϫ mice showed the absence of dorsal limb structures and duplication of ventral structures (7). These findings suggest that Lmx1b is essential for dorsoventral patterning during development and that the skeletal phenotype of NPS is the result of a deficiency in dorsoventral patterning. LMX1B is also expressed in human fetal and adult kidneys (5).From the analysis of Lmx1bϪ/Ϫ mice, it was suggested that LMX1B regulates the expression of type IV collagen ␣3 and ␣4 and podocin and that Lmx1b mutations cause disruption of these proteins, resulting in...

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Molecular Genetics of Nail–Patella Syndrome

McIntosh¹

2012

Encyclopedia of Life Sciences

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Nail–patella Syndrome (NPS) is a pleiotropic disorder affecting development of the limbs, kidneys, eyes and central nervous system, which is the result of heterozygous, loss‐of‐function mutations in the transcription factor, LIM‐homeobox 1β (LMX1B). There is no correlation between the type or nature of individual mutations and the severity of the phenotype. The availability of animal models, together with analysis of gene expression patterns during development, has substantiated that the range of clinically relevant signs and symptoms is greater than appreciated previously. Evidence is building that attention deficit±hyperactivity disorder and depression may be constituent parts of the syndrome. The variation in the range and severity of symptoms, and the diverse range of affected tissues, make NPS an appropriate model in which to study the effects of gene interactions on the observed phenotype. Key Concepts: NPS is a pleiotropic, clinically variable autosomal dominant disorder. LMX1B is a member of a gene family primarily involved in regulating neuronal patterning. Loss of function mutations in LMX1B cause NPS but do not predict disease severity. Analysis of Lmx1b expression has helped explain previously unknown neural aspects of NPS. Physicians should be aware of the extra‐skeletal aspects of NPS and institute appropriate monitoring and treatment.

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LMX1B transactivation and expression in nail-patella syndrome

Cited by 94 publications

References 29 publications

Lmx1b and FoxC Combinatorially Regulate Podocin Expression in Podocytes

Lmx1b and FoxC Combinatorially Regulate Podocin Expression in Podocytes

Functional Characterization of LMX1B Mutations Associated with Nail-Patella Syndrome

Molecular Genetics of Nail–Patella Syndrome

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