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Jürgen Kohlhase - One of the best experts on this subject based on the ideXlab platform.
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SALL1, Sall2, and Sall4 Are Required for Neural Tube Closure in Mice
The American journal of pathology, 2008Co-Authors: Johann Böhm, Anja Buck, Wiktor Borozdin, Ashraf U. Mannan, Uta Matysiak-scholze, Ibrahim M. Adham, Walter J. Schulz-schaeffer, Thomas Floss, Wolfgang Wurst, Jürgen KohlhaseAbstract:Four homologs to the Drosophila homeotic gene spalt (sal) exist in both humans and mice (SALL1 to SALL4/SALL1 to Sall4, respectively). Mutations in both SALL1 and SALL4 result in the autosomal-dominant developmental disorders Townes-Brocks and Okihiro syndrome, respectively. In contrast, no human diseases have been associated with SALL2 to date, and Sall2-deficient mice have shown no apparent abnormal phenotype. We generated mice deficient in Sall2 and, contrary to previous reports, 11% of our Sall2-deficient mice showed background-specific neural tube defects, suggesting that Sall2 has a role in neurogenesis. To investigate whether Sall4 may compensate for the absence of Sall2, we generated compound Sall2 knockout/Sall4 genetrap mutant mice. In these mutants, the incidence of neural tube defects was significantly increased. Furthermore, we found a similar phenotype in compound SALL1/4 mutant mice, and in vitro studies showed that SALL1, SALL2, and SALL4 all co-localized in the nucleus. We therefore suggest a fundamental and redundant function of the Sall proteins in murine neurulation, with the heterozygous loss of a particular SALL protein also possibly compensated in humans during development.
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SALL1 mutations in sporadic Townes-Brocks syndrome are of predominantly paternal origin without obvious paternal age effect.
American journal of medical genetics. Part A, 2006Co-Authors: Johann Böhm, Susanne Munk-schulenburg, Stephanie Felscher, Jürgen KohlhaseAbstract:Autosomal dominant Townes–Brocks syndrome (TBS) is characterized by imperforate anus, triphalangeal and supernumerary thumbs, dysplastic ears and sensorineural hearing loss, and may also involve other organ systems. Strong inter- and intrafamiliar variability is known. Approximately 50% of TBS cases are sporadic and due to de novo mutations in the SALL1 gene. SALL1 encodes a zinc finger protein operating as a transcriptional repressor and localizing to pericentromeric heterochromatin. We traced the parental origin of SALL1 mutations in sporadic TBS by analysis of linkage between SALL1 mutations and exonic or intronic polymorphisms in 16 families with 10 different mutations. Mutations were of paternal origin in 14 of 16 cases (87.5%). Paternal origin was independent of the mutation type. The mean paternal age at conception was 29.9 and the mean maternal age 26.5 years. We conclude that de novo mutations in SALL1 mostly occur on the paternally derived chromosome 16 without an obvious age effect. © 2006 Wiley-Liss, Inc.
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Defining the heterochromatin localization and repression domains of SALL1.
Biochimica et biophysica acta, 2006Co-Authors: Christian Netzer, Stefan K. Bohlander, Markus Hinzke, Ying Chen, Jürgen KohlhaseAbstract:Abstract SALL1 has been identified as one of four human homologues of the Drosophila region-specific homeotic gene spalt (sal), encoding zinc finger proteins of characteristic structure. Mutations of SALL1 on chromosome 16q12.1 cause Townes–Brocks syndrome (TBS, OMIM 107480). We have shown previously that SALL1 acts as a strong transcriptional repressor in mammalian cells when fused to a heterologous DNA-binding domain. Here, we report that SALL1 contains two repression domains, one located at the extreme N-terminus of the protein and the other in the central region. SALL1 fragments with the central repression domain exhibited a punctate nuclear distribution pattern at pericentromeric heterochromatin foci in murine NIH-3T3 cells, suggesting an association between repression and heterochromatin localization. The implications of these findings for the pathogenesis of Townes–Brocks syndrome are discussed.
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Detection of heterozygous SALL1 deletions by quantitative real time PCR proves the contribution of a SALL1 dosage effect in the pathogenesis of Townes-Brocks syndrome.
Human mutation, 2006Co-Authors: Wiktor Borozdin, Katharina Steinmann, Beate Albrecht, Armand Bottani, Koenraad Devriendt, Michael Leipoldt, Jürgen KohlhaseAbstract:Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited disorder characterized by ear, anal, limb, and renal malformations, and results from mutations in the gene SALL1. All SALL1 mutations previously found in TBS patients create preterminal termination codons. In accordance with the findings of pericentric inversions or balanced translocations, TBS was initially assumed to be caused by SALL1 haploinsufficiency. This assumption was strongly contradicted by a SALL1 mouse knock-out, because neither hetero- nor homozygous knock-out mutants displayed a TBS-like phenotype. A different mouse mutant mimicking the human SALL1 mutations, however, showed a TBS-like phenotype in the heterozygous situation, suggesting a dominant-negative action of the mutations causing TBS. We applied quantitative real time PCR to detect and map SALL1 deletions in 240 patients with the clinical diagnosis of TBS, who were negative for SALL1 mutations. Deletions were found in three families. In the first family, a 75 kb deletion including all SALL1 exons had been inherited by two siblings from their father. A second, sporadic patient carried a de novo 1.9-2.6 Mb deletion including the whole SALL1 gene, and yet another sporadic case was found to carry an intragenic deletion of 3384 bp. In all affected persons, the TBS phenotype is rather mild as compared to the phenotype resulting from point mutations. These results confirm that SALL1 haploinsufficiency is sufficient to cause a mild TBS phenotype but suggest that it is not sufficient to cause the severe, classical form. It therefore seems that there is a different contribution of SALL1 gene function to mouse and human embryonic development.
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expression of a truncated SALL1 transcriptional repressor is responsible for townes brocks syndrome birth defects
Human Molecular Genetics, 2003Co-Authors: Susan M. Kiefer, Jürgen Kohlhase, Kevin K. Ohlemiller, Jing Yang, Bradley W. Mcdill, Michael RauchmanAbstract:Townes-Brocks syndrome (TBS, OMIM #107480) is an autosomal dominant disorder that causes multiple birth defects including renal, ear, anal and limb malformations. Mutations in SALL1 have been postulated to cause TBS by haploinsufficiency; however, a mouse model carrying a SALL1-null allele does not mimic the human syndrome. Since the mutations that cause TBS could express a truncated SALL1 protein containing the domain necessary for transcriptional repression but lacking the complete DNA binding domain, we hypothesized that TBS is due to dominant-negative or gain-of-function activity of a mutant protein. To test this hypothesis, we have created a mutant allele, SALL1-DeltaZn2-10, that produces a truncated protein and recapitulates the abnormalities found in human TBS. Heterozygous mice mimic TBS patients by displaying high-frequency sensorineural hearing loss, renal cystic hypoplasia and wrist bone abnormalities. Homozygous SALL1-DeltaZn2-10 mutant mice exhibit more severe defects than SALL1-null mice including complete renal agenesis, exencephaly, limb and anal deformities. We demonstrate that truncated SALL1 mediates interaction with all Sall family members and could interfere with the normal function of all Sall proteins. These data support a model for the pathogenesis of TBS in which expression of a truncated SALL1 protein causes abnormal development of multiple organs.
Ryuichi Nishinakamura - One of the best experts on this subject based on the ideXlab platform.
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SALL1 Regulates Microglial Morphology Cell Autonomously in the Developing Retina.
Advances in experimental medicine and biology, 2018Co-Authors: Hideto Koso, Ryuichi Nishinakamura, Sumiko WatanabeAbstract:Retinal degeneration often accompanies microglial activation and infiltration of monocyte-derived macrophages into the retina, resulting in the coexistence of microglia and monocyte-derived macrophages in the retina. We previously showed that the SALL1 zinc-finger transcriptional factor is expressed specifically in microglia within the retinal phagocyte pool, and analyses of SALL1 knockout mice revealed that microglial morphology changed from a ramified to a more amoeboid appearance in the developing retina. To investigate further whether SALL1 functions autonomously in microglia, we generated SALL1 conditional knockout mice, in which SALL1 was depleted specifically in the Cx3cr1+ microglial compartment of the developing retina. SALL1-deficient microglia exhibited morphological abnormalities on embryonic day 18 that strikingly resembled the phenotype observed in SALL1 knockout mice, demonstrating that SALL1 regulates microglial morphology cell autonomously. Analysis of the postnatal retina revealed that SALL1-deficient microglia extended their processes and their morphology became comparable to that of wild-type microglia on postnatal day 21, indicating that SALL1 is essential for microglial ramification in the developing retina, but not in the postnatal retina.
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SALL1 is a transcriptional regulator defining microglia identity and function
Nature immunology, 2016Co-Authors: Anne Buttgereit, Ryuichi Nishinakamura, Iva Lelios, Melissa Vrohlings, Natalie R Krakoski, Emmanuel L. Gautier, Burkhard Becher, Melanie GreterAbstract:Microglia are the resident macrophages of the central nervous system (CNS). Gene expression profiling has identified SALL1, which encodes a transcriptional regulator, as a microglial signature gene. We found that SALL1 was expressed by microglia but not by other members of the mononuclear phagocyte system or by other CNS-resident cells. Using SALL1 for microglia-specific gene targeting, we found that the cytokine receptor CSF1R was involved in the maintenance of adult microglia and that the receptor for the cytokine TGF-β suppressed activation of microglia. We then used the microglia-specific expression of SALL1 to inducibly inactivate the murine SALL1 locus in vivo, which resulted in the conversion of microglia from resting tissue macrophages into inflammatory phagocytes, leading to altered neurogenesis and disturbed tissue homeostasis. Collectively, our results show that transcriptional regulation by SALL1 maintains microglial identity and physiological properties in the CNS and allows microglia-specific manipulation in vivo.
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SALL1 in renal stromal progenitors non-cell autonomously restricts the excessive expansion of nephron progenitors.
Scientific reports, 2015Co-Authors: Tomoko Ohmori, Shunsuke Tanigawa, Sayoko Fujimura, Yusuke Kaku, Ryuichi NishinakamuraAbstract:The mammalian kidney develops from reciprocal interactions between the metanephric mesenchyme and ureteric bud, the former of which contains nephron progenitors. The third lineage, the stroma, fills up the interstitial space and is derived from distinct progenitors that express the transcription factor Foxd1. We showed previously that deletion of the nuclear factor SALL1 in nephron progenitors leads to their depletion in mice. However, SALL1 is expressed not only in nephron progenitors but also in stromal progenitors. Here we report that specific SALL1 deletion in stromal progenitors leads to aberrant expansion of nephron progenitors, which is in sharp contrast with a nephron progenitor-specific deletion. The mutant mice also exhibited cystic kidneys after birth and died before adulthood. We found that Decorin, which inhibits Bmp-mediated nephron differentiation, was upregulated in the mutant stroma. In contrast, the expression of Fat4, which restricts nephron progenitor expansion, was reduced mildly. Furthermore, the SALL1 protein binds to many stroma-related gene loci, including Decorin and Fat4. Thus, the expression of SALL1 in stromal progenitors restricts the excessive expansion of nephron progenitors in a non-cell autonomous manner, and SALL1-mediated regulation of Decorin and Fat4 might at least partially underlie the pathogenesis.
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Sall4 Is Transiently Expressed in the Caudal Wolffian Duct and the Ureteric Bud, but Dispensable for Kidney Development
PloS one, 2013Co-Authors: Daichi Toyoda, Tomoko Ohmori, Atsuhiro Taguchi, Masahiko Chiga, Ryuichi NishinakamuraAbstract:The kidney, the metanephros, is formed by reciprocal interactions between the metanephric mesenchyme and the ureteric bud, the latter of which is derived from the Wolffian duct that elongates in the rostral-to-caudal direction. SALL1 expressed in the metanephric mesenchyme is essential for ureteric bud attraction in kidney development. Sall4, another member of the Sall gene family, is required for maintenance of embryonic stem cells and establishment of induced pluripotent stem cells, and is thus considered to be one of the stemness genes. Sall4 is also a causative gene for Okihiro syndrome and is essential for the formation of many organs in both humans and mice. However, its expression and role in kidney development remain unknown, despite the essential role of SALL1 in the metanephric mesenchyme. Here, we report that mouse Sall4 is expressed transiently in the Wolffian duct-derived lineage, and is nearly complementary to SALL1 expression. While Sall4 expression is excluded from the Wolffian duct at embryonic (E) day 9.5, Sall4 is expressed in the Wolffian duct weakly in the mesonephric region at E10.5 and more abundantly in the caudal metanephric region where ureteric budding occurs. Sall4 expression is highest at E11.5 in the Wolffian duct and ureteric bud, but disappears by E13.5. We further demonstrate that Sall4 deletion in the Wolffian duct and ureteric bud does not cause any apparent kidney phenotypes. Therefore, Sall4 is expressed transiently in the caudal Wolffian duct and the ureteric bud, but is dispensable for kidney development in mice.
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SALL1 regulates cortical neurogenesis and laminar fate specification in mice: implications for neural abnormalities in Townes-Brocks syndrome
Disease models & mechanisms, 2011Co-Authors: Susan J. Harrison, Ryuichi Nishinakamura, Kevin R. Jones, A. Paula MonaghanAbstract:Progenitor cells in the cerebral cortex undergo dynamic cellular and molecular changes during development. SALL1 is a putative transcription factor that is highly expressed in progenitor cells during development. In humans, the autosomal dominant developmental disorder Townes-Brocks syndrome (TBS) is associated with mutations of the SALL1 gene. TBS is characterized by renal, anal, limb and auditory abnormalities. Although neural deficits have not been recognized as a diagnostic characteristic of the disease, ~10% of patients exhibit neural or behavioral abnormalities. We demonstrate that, in addition to being expressed in peripheral organs, SALL1 is robustly expressed in progenitor cells of the central nervous system in mice. Both classical- and conditional-knockout mouse studies indicate that the cerebral cortex is particularly sensitive to loss of SALL1. In the absence of SALL1, both the surface area and depth of the cerebral cortex were decreased at embryonic day 18.5 (E18.5). These deficiencies are associated with changes in progenitor cell properties during development. In early cortical progenitor cells, SALL1 promotes proliferative over neurogenic division, whereas, at later developmental stages, SALL1 regulates the production and differentiation of intermediate progenitor cells. Furthermore, SALL1 influences the temporal specification of cortical laminae. These findings present novel insights into the function of SALL1 in the developing mouse cortex and provide avenues for future research into potential neural deficits in individuals with TBS.
Michael Rauchman - One of the best experts on this subject based on the ideXlab platform.
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Analysis of FGF20-regulated genes in organ of Corti progenitors by translating ribosome affinity purification.
Developmental dynamics : an official publication of the American Association of Anatomists, 2020Co-Authors: Lu M. Yang, Michael Rauchman, Lisa Stout, David M. OrnitzAbstract:BACKGROUND Understanding the mechanisms that regulate hair cell (HC) differentiation in the organ of Corti (OC) is essential to designing genetic therapies for hearing loss due to HC loss or damage. We have previously identified Fibroblast Growth Factor 20 (FGF20) as having a key role in HC and supporting cell differentiation in the mouse OC. To investigate the genetic landscape regulated by FGF20 signaling in OC progenitors, we employ Translating Ribosome Affinity Purification combined with Next Generation RNA Sequencing (TRAPseq) in the Fgf20 lineage. RESULTS We show that TRAPseq targeting OC progenitors effectively enriched for RNA from this rare cell population. TRAPseq identified differentially expressed genes (DEGs) downstream of FGF20, including Etv4, Etv5, Etv1, Dusp6, Hey1, Hey2, Heyl, Tectb, Fat3, Cpxm2, SALL1, Sall3, and cell cycle regulators such as Cdc20. Analysis of Cdc20 conditional-null mice identified decreased cochlea length, while analysis of SALL1-null and SALL1-ΔZn2-10 mice, which harbor a mutation that causes Townes-Brocks syndrome, identified a decrease in outer hair cell number. CONCLUSIONS We present two datasets: genes with enriched expression in OC progenitors, and DEGs downstream of FGF20 in the embryonic day 14.5 cochlea. We validate select DEGs via in situ hybridization and in vivo functional studies in mice.
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SALL1 expression in acute myeloid leukemia
Oncotarget, 2017Co-Authors: Huda S. Salman, Michael Rauchman, Lynn Robbins, Xiao Shuai, Anh Thu Nguyen-lefebvre, Banabihari Giri, Mingqiang Ren, Wei Hou, Hasan KorkayaAbstract:// Huda Salman 1, 2 , Xiao Shuai 2, 3, * , Anh Thu Nguyen-Lefebvre 1, * , Banabihari Giri 1 , Mingqiang Ren 1 , Michael Rauchman 4 , Lynn Robbins 4 , Wei Hou 2 , Hasan Korkaya 1 and Yupo Ma 2 1 Georgia Regent University Cancer Center, Augusta, GA, USA 2 Present address: Stony Brook University Cancer Center, Stony Brook, NY, USA 3 Department of Hematology, West China hospital of Sichuan University, Chengdu, P.R. China 4 Department of Nephrology, Saint Louis University, St Louis, MO, USA * These authors contributed equally to this work Correspondence to: Huda Salman, email: huda.salman@stonybrookmedicine.edu Keywords: SALL1; AML Received: August 18, 2017 Accepted: October 25, 2017 Published: December 15, 2017 ABSTRACT Similar signaling pathways could operate in both normal hematopoietic stem and progenitor cells (HSPCs) and leukemia stem cells (LSCs). Thus, targeting LSCs signaling without substantial toxicities to normal HSPCs remains challenging. SALL1, is a member of the transcriptional network that regulates stem cell pluripotency, and lacks significant expression in most adult tissues, including normal bone marrow (NBM). We examined the expression and functional characterization of SALL1 in NBM and in acute myeloid leukemia (AML) using in vitro and in vivo assays. We showed that SALL1 is expressed preferentially in LSCs- enriched CD34+CD38- cell subpopulation but not in NBM. SALL1 inhibition resulted in decreased cellular proliferation and in inferior AML engraftment in NSG mice and it was also associated with upregulation of PTEN and downregulation of m-TOR, β-catenin, and NF- қB expression. These findings suggest that SALL1 inhibition interrupts leukemogenesis. Further studies to validate SALL1 as a potential biomarker for minimal residual disease (MRD) and to determine SALL1’s role in prognostication are ongoing. Additionally, pre-clinical evaluation of SALL1 as a therapeutic target in AML is warranted.
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SALL1 balances self-renewal and differentiation of renal progenitor cells.
Development, 2014Co-Authors: Jeannine Basta, Susan M. Kiefer, Lynn Robbins, Dale Dorsett, Michael RauchmanAbstract:The formation of the proper number of functional nephrons requires a delicate balance between renal progenitor cell self-renewal and differentiation. The molecular factors that regulate the dramatic expansion of the progenitor cell pool and differentiation of these cells into nephron precursor structures (renal vesicles) are not well understood. Here we show that SALL1, a nuclear transcription factor, is required to maintain the stemness of nephron progenitor cells. Transcriptional profiling of SALL1 mutant cells revealed a striking pattern, marked by the reduction of progenitor genes and amplified expression of renal vesicle differentiation genes. These global changes in gene expression were accompanied by ectopic differentiation at E12.5 and depletion of Six2+Cited1+ cap mesenchyme progenitor cells. These findings highlight a novel role for SALL1 in maintaining the stemness of the progenitor cell pool by restraining their differentiation into renal vesicles.
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Mi-2/NuRD is required in renal progenitor cells during embryonic kidney development
Developmental Biology, 2012Co-Authors: D.r. Denner, Michael RauchmanAbstract:Development of the nephron tubules, the functional units of the kidney, requires the differentiation of a renal progenitor population of mesenchymal cells to epithelial cells. This process requires an intricate balance between self-renewal and differentiation of the renal progenitor pool. SALL1 is a transcription factor necessary for renal development which is expressed in renal progenitor cells (cap mesenchyme). SALL1 recruits the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex to regulate gene transcription. We deleted Mi2β, a component of the NuRD complex, in cap mesenchyme (CM) to examine its role in progenitor cells during kidney development. These mutants displayed significant renal hypoplasia with a marked reduction in nephrons. Markers of renal progenitor cells, Six2 and Cited1 were significantly depleted and progenitor cell proliferation was reduced. We also demonstrated that SALL1 and Mi2β exhibited a strong in vivo genetic interaction in the developing kidney. Together these findings indicate that SALL1 and NuRD act cooperatively to maintain CM progenitor cells.
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SALL1-dependent signals affect Wnt signaling and ureter tip fate to initiate kidney development
Development (Cambridge England), 2010Co-Authors: Susan M. Kiefer, Lynn Robbins, Kelly M. Stumpff, Congxing Lin, Michael RauchmanAbstract:Development of the metanephric kidney depends on precise control of branching of the ureteric bud. Branching events represent terminal bifurcations that are thought to depend on unique patterns of gene expression in the tip compared with the stalk and are influenced by mesenchymal signals. The metanephric mesenchyme-derived signals that control gene expression at the ureteric bud tip are not well understood. In mouse SALL1 mutants, the ureteric bud grows out and invades the metanephric mesenchyme, but it fails to initiate branching despite tip-specific expression of Ret and Wnt11. The stalk-specific marker Wnt9b and the β-catenin downstream target Axin2 are ectopically expressed in the mutant ureteric bud tips, suggesting that upregulated canonical Wnt signaling disrupts ureter branching in this mutant. In support of this hypothesis, ureter arrest is rescued by lowering β-catenin levels in the SALL1 mutant and is phenocopied by ectopic expression of a stabilized β-catenin in the ureteric bud. Furthermore, transgenic overexpression of Wnt9b in the ureteric bud causes reduced branching in multiple founder lines. These studies indicate that SALL1-dependent signals from the metanephric mesenchyme are required to modulate ureteric bud tip Wnt patterning in order to initiate branching.
Susan M. Kiefer - One of the best experts on this subject based on the ideXlab platform.
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SALL1 functions as a tumor suppressor in breast cancer by regulating cancer cell senescence and metastasis through the NuRD complex.
Molecular cancer, 2018Co-Authors: Fang Wang, Susan M. Kiefer, Lynn Robbins, Bing Han, Xiaoli Zhong, Eddy C. Hsueh, Yanping ZhangAbstract:SALL1 is a multi-zinc finger transcription factor that regulates organogenesis and stem cell development, but the role of SALL1 in tumor biology and tumorigenesis remains largely unknown. We analyzed SALL1 expression levels in human and murine breast cancer cells as well as cancer tissues from different types of breast cancer patients. Using both in vitro co-culture system and in vivo breast tumor models, we investigated how SALL1 expression in breast cancer cells affects tumor cell growth and proliferation, metastasis, and cell fate. Using the gain-of function and loss-of-function strategies, we dissected the molecular mechanism responsible for SALL1 tumor suppressor functions. We demonstrated that SALL1 functions as a tumor suppressor in breast cancer, which is significantly down-regulated in the basal like breast cancer and in estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2) triple negative breast cancer patients. SALL1 expression in human and murine breast cancer cells inhibited cancer cell growth and proliferation, metastasis, and promoted cell cycle arrest. Knockdown of SALL1 in breast cancer cells promoted cancer cell growth, proliferation, and colony formation. Our studies revealed that tumor suppression was mediated by recruitment of the Nucleosome Remodeling and Deacetylase (NuRD) complex by SALL1, which promoted cancer cell senescence. We further demonstrated that the mechanism of inhibition of breast cancer cell growth and invasion by SALL1-NuRD depends on the p38 MAPK, ERK1/2, and mTOR signaling pathways. Our studies indicate that the developmental control gene SALL1 plays a critical role in tumor suppression by recruiting the NuRD complex and thereby inducing cell senescence in breast cancer cells.
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SALL1 functions as a tumor suppressor in breast cancer by regulating cancer cell senescence and metastasis through the NuRD complex
BMC, 2018Co-Authors: Fang Wang, Susan M. Kiefer, Lynn Robbins, Bing Han, Xiaoli Zhong, Eddy C. Hsueh, Yanping ZhangAbstract:Abstract Background SALL1 is a multi-zinc finger transcription factor that regulates organogenesis and stem cell development, but the role of SALL1 in tumor biology and tumorigenesis remains largely unknown. Methods We analyzed SALL1 expression levels in human and murine breast cancer cells as well as cancer tissues from different types of breast cancer patients. Using both in vitro co-culture system and in vivo breast tumor models, we investigated how SALL1 expression in breast cancer cells affects tumor cell growth and proliferation, metastasis, and cell fate. Using the gain-of function and loss-of-function strategies, we dissected the molecular mechanism responsible for SALL1 tumor suppressor functions. Results We demonstrated that SALL1 functions as a tumor suppressor in breast cancer, which is significantly down-regulated in the basal like breast cancer and in estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2) triple negative breast cancer patients. SALL1 expression in human and murine breast cancer cells inhibited cancer cell growth and proliferation, metastasis, and promoted cell cycle arrest. Knockdown of SALL1 in breast cancer cells promoted cancer cell growth, proliferation, and colony formation. Our studies revealed that tumor suppression was mediated by recruitment of the Nucleosome Remodeling and Deacetylase (NuRD) complex by SALL1, which promoted cancer cell senescence. We further demonstrated that the mechanism of inhibition of breast cancer cell growth and invasion by SALL1-NuRD depends on the p38 MAPK, ERK1/2, and mTOR signaling pathways. Conclusion Our studies indicate that the developmental control gene SALL1 plays a critical role in tumor suppression by recruiting the NuRD complex and thereby inducing cell senescence in breast cancer cells
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SALL1 balances self-renewal and differentiation of renal progenitor cells.
Development, 2014Co-Authors: Jeannine Basta, Susan M. Kiefer, Lynn Robbins, Dale Dorsett, Michael RauchmanAbstract:The formation of the proper number of functional nephrons requires a delicate balance between renal progenitor cell self-renewal and differentiation. The molecular factors that regulate the dramatic expansion of the progenitor cell pool and differentiation of these cells into nephron precursor structures (renal vesicles) are not well understood. Here we show that SALL1, a nuclear transcription factor, is required to maintain the stemness of nephron progenitor cells. Transcriptional profiling of SALL1 mutant cells revealed a striking pattern, marked by the reduction of progenitor genes and amplified expression of renal vesicle differentiation genes. These global changes in gene expression were accompanied by ectopic differentiation at E12.5 and depletion of Six2+Cited1+ cap mesenchyme progenitor cells. These findings highlight a novel role for SALL1 in maintaining the stemness of the progenitor cell pool by restraining their differentiation into renal vesicles.
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SALL1-dependent signals affect Wnt signaling and ureter tip fate to initiate kidney development
Development (Cambridge England), 2010Co-Authors: Susan M. Kiefer, Lynn Robbins, Kelly M. Stumpff, Congxing Lin, Michael RauchmanAbstract:Development of the metanephric kidney depends on precise control of branching of the ureteric bud. Branching events represent terminal bifurcations that are thought to depend on unique patterns of gene expression in the tip compared with the stalk and are influenced by mesenchymal signals. The metanephric mesenchyme-derived signals that control gene expression at the ureteric bud tip are not well understood. In mouse SALL1 mutants, the ureteric bud grows out and invades the metanephric mesenchyme, but it fails to initiate branching despite tip-specific expression of Ret and Wnt11. The stalk-specific marker Wnt9b and the β-catenin downstream target Axin2 are ectopically expressed in the mutant ureteric bud tips, suggesting that upregulated canonical Wnt signaling disrupts ureter branching in this mutant. In support of this hypothesis, ureter arrest is rescued by lowering β-catenin levels in the SALL1 mutant and is phenocopied by ectopic expression of a stabilized β-catenin in the ureteric bud. Furthermore, transgenic overexpression of Wnt9b in the ureteric bud causes reduced branching in multiple founder lines. These studies indicate that SALL1-dependent signals from the metanephric mesenchyme are required to modulate ureteric bud tip Wnt patterning in order to initiate branching.
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The Sal-Like 1 (SALL1) Protein is Highly Expressed in Primary Bone Marrow Cells Derived From Patients with Acute Myeloid Leukemia.
Blood, 2009Co-Authors: Heiko Konig, Susan M. Kiefer, Michael Rauchman, Lynn Robbins, Huda S. SalmanAbstract:Abstract 1285 Poster Board I-307 Background SALL1 is a zinc finger transcription factor that maps to chromosome 16q12.1 in humans and chromosome 8D in mice. It is a transcription factor required for kidney development, and is mutated in patients with Townes-Brocks syndrome (TBS). We have created a mouse model of TBS that expresses a truncated SALL1 protein and observed that these mice displayed a syndrome consistent with myelodysplastic syndrome (MDS) that accelerates to acute myeloid leukemia (AML). The purpose of this study was to investigate whether SALL1 is expressed in AML patients. Materials and methods 50 bone marrow (BM) samples obtained from AML patients and 10 BM samples obtained from healthy donors were studied. BM samples were processed immediately upon receipt. Immunohistochemistry was performed on paraffin tissue sections of human BM using an anti-SALL1 antibody. RNA was extracted using the RNeasy Mini Kit (Qiagen). Quantitative RT-PCR was performed using the SYBR Green PCR Master Mix and SALL1 specific primers. SALL1 mRNA expression was normalized to RPL19, a ribosomal housekeeping gene. Western blotting was performed to confirm the presence of SALL1 at the protein level. Two AML cell lines (Kasumi-1 and -3) were also screened for SALL1 expression. Results 44/50 human BM AML samples displayed positive nuclear staining for SALL1. Samples taken from healthy controls showed no evidence of staining. 9/ 9 human BM AML samples showed increased SALL1 mRNA levels as compared to healthy controls with upregulation of SALL1 mRNA levels ranging from 3-fold to 1630-fold. High interpatient variability was observed. On average, SALL1 expression of AML patients was 225.1-fold greater than that of healthy controls (n=9, p=0.004). Western blotting confirmed upregulated SALL1 protein expression in AML BM with no expression seen in healthy controls. No SALL1 mRNA was detected in Kasumi-1 and -3 AML cell lines. i.) The majority of patient samples examined in this study demonstrated positive staining for SALL1. ii.) Consistent with its role as a transcription factor SALL1 histochemical staining was nuclear. iii.) SALL1 is highly expressed in human AML BM on the mRNA as well as on the protein level. iv.) No SALL1 mRNA was detected in AML cell lines. Conclusion Our data in mice and humans link the overexpression of SALL1 to AML. The absence of SALL1 in cell lines and its presence in the BM may indicate that SALL1 is confined to a relatively primitive cell. It is to be speculated that SALL1 has functional significance for the molecular pathogenesis of AML. Further studies to elaborate on its molecular functions and interactions are therefore clearly warranted and being conducted. Disclosures No relevant conflicts of interest to declare.
Bruce R Korf - One of the best experts on this subject based on the ideXlab platform.
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townes brocks syndrome versus expanded spectrum hemifacial microsomia review of eight patients and further evidence of a hot spot for mutation in the SALL1 gene
Genetics in Medicine, 2001Co-Authors: Catherine E Keegan, John B Mulliken, Bruce R KorfAbstract:Townes-Brocks syndrome versus expanded spectrum hemifacial microsomia: Review of eight patients and further evidence of a “hot spot” for mutation in the SALL1 gene
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Townes-Brocks syndrome versus expanded spectrum hemifacial microsomia: Review of eight patients and further evidence of a “hot spot” for mutation in the SALL1 gene
Genetics in medicine : official journal of the American College of Medical Genetics, 2001Co-Authors: Catherine E Keegan, John B Mulliken, Bruce R KorfAbstract:Townes-Brocks syndrome versus expanded spectrum hemifacial microsomia: Review of eight patients and further evidence of a “hot spot” for mutation in the SALL1 gene
