CITED1 Expression in Wilms' Tumor and Embryonic Kidney

Lovvorn, Harold N.; Westrup, Jenifer; Opperman, Shaun; Boyle, Scott; Shit, Genbin; Anderson, James R.; Perlman, Elizabeth J.; Perantoni, Alan O.; Wills, Marcia L.; Caestecker, Mark P. de

doi:10.1593/neo.07358

Cited by 34 publications

(47 citation statements)

References 40 publications

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“…Failure in FGF/EGF feedback control by genes such as Sprouty might contribute to the undifferentiated metanephric blastema found in Wilms' tumor, where the advanced stage of the disease is known to be correlated with persistent expression of early blastemal markers such as Cited1 and Meox1 (Williams et al, 2004;Li et al, 2005;Lovvorn et al, 2007a;Lovvorn et al, 2007b). The FGF/EGF signaling pathway components that are disrupted by Spry1, or genes that alter Spry1 activity, might represent novel therapeutic targets to combat Wilms' tumor and other cancers that arise from parent stem cells that normally display a requirement for FGF signaling during self-renewal.…”

Section: Research Articlementioning

confidence: 99%

FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development

et al. 2011

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SUMMARYRecent studies indicate that nephron progenitor cells of the embryonic kidney are arranged in a series of compartments of an increasing state of differentiation. The earliest progenitor compartment, distinguished by expression of CITED1, possesses greater capacity for renewal and differentiation than later compartments. Signaling events governing progression of nephron progenitor cells through stages of increasing differentiation are poorly understood, and their elucidation will provide key insights into normal and dysregulated nephrogenesis, as well as into regenerative processes that follow kidney injury. In this study, we found that the mouse CITED1 + progenitor compartment is maintained in response to receptor tyrosine kinase (RTK) ligands that activate both FGF and EGF receptors. This RTK signaling function is dependent on RAS and PI3K signaling but not ERK. In vivo, RAS inactivation by expression of sprouty 1 (Spry1) in CITED1 + nephron progenitors results in loss of characteristic molecular marker expression and in increased death of progenitor cells. Lineage tracing shows that surviving Spry1-expressing progenitor cells are impaired in their subsequent epithelial differentiation, infrequently contributing to epithelial structures. These findings demonstrate that the survival and developmental potential of cells in the earliest embryonic nephron progenitor cell compartment are dependent on FGF/EGF signaling through RAS.

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Section: Research Articlementioning

confidence: 99%

FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development

et al. 2011

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“…The tumors are characterized by blastemal, epithelial and stromal elements much like the developing kidney. The blastema displays nephron progenitor-like characteristics, expressing factors such as CITED1, SIX1 and SIX2 (Li et al, 2002;Lovvorn et al, 2007;Murphy et al, 2012;Sehic et al, 2012Sehic et al, , 2014. Mutations in the DNA binding homeodomain of SIX1 and SIX2 are associated with chemotherapy-resistant blastemas, suggesting that these mutations might contribute to an aggressive etiology of such tumors (Wegert et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators

et al. 2016

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Nephron endowment is determined by the self-renewal and induction of a nephron progenitor pool established at the onset of kidney development. In the mouse, the related transcriptional regulators Six1 and Six2 play non-overlapping roles in nephron progenitors. Transient Six1 activity prefigures, and is essential for, active nephrogenesis. By contrast, Six2 maintains later progenitor selfrenewal from the onset of nephrogenesis. We compared the regulatory actions of Six2 in mouse and human nephron progenitors by chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq). Surprisingly, SIX1 was identified as a SIX2 target unique to the human nephron progenitors. Furthermore, RNAseq and immunostaining revealed overlapping SIX1 and SIX2 activity in 16 week human fetal nephron progenitors. Comparative bioinformatic analysis of human SIX1 and SIX2 ChIP-seq showed each factor targeted a similar set of cis-regulatory modules binding an identical target recognition motif. In contrast to the mouse where Six2 binds its own enhancers but does not interact with DNA around Six1, both human SIX1 and SIX2 bind homologous SIX2 enhancers and putative enhancers positioned around SIX1. Transgenic analysis of a putative human SIX1 enhancer in the mouse revealed a transient, mouse-like, pre-nephrogenic, Six1 regulatory pattern. Together, these data demonstrate a divergence in SIX-factor regulation between mouse and human nephron progenitors. In the human, an auto/cross-regulatory loop drives continued SIX1 and SIX2 expression during active nephrogenesis. By contrast, the mouse establishes only an auto-regulatory Six2 loop. These data suggest differential SIX-factor regulation might have contributed to species differences in nephron progenitor programs such as the duration of nephrogenesis and the final nephron count.

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“…CD56 (NCAM), which has been proposed to be specific for the blastemal compartment of WT (Roth et al, 1988;Muir et al, 2001), was not observed in any WT culture, while all primary cells expressed CITED1, another proposed blastemal marker (Lovvorn et al, 2007). Cytokeratin staining (Cam5.2), which is specific for the epithelial component of WT tissue, distinguished two types of WT cultures (Fig.…”

Section: Primary Wt Culturesmentioning

confidence: 87%

Characterization of primary wilms tumor cultures as an in vitro model

Wegert¹,

Bausenwein²,

Roth

et al. 2011

Genes Chromosomes & Cancer

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Functional analysis of gene candidates and testing of novel therapeutics in Wilms tumors (WT) has been hampered by the lack of in vitro model systems. WT are characterized by a spectrum of histological appearances, but published cell lines are mostly derived from rare anaplastic variants or even non-WT. There has been some success in establishing primary cultures, but these are often poorly characterized or only derived from less frequent WT1 mutant tumors. We report the generation of a set of primary WT-cell cultures using a simple cultivation protocol. Our cultures could be established after preoperative chemotherapy and irrespective of histological subtypes or genetic alterations. The presence of tumor-specific genetic alterations validates these cultures as being tumor-derived. Genetic characterization is of utmost importance as some cultures with similar morphological appearance lacked such alterations and either represent clonal variants or normal cells. By immunohistochemistry, the cells are either epithelial or more mesenchymal, and the latter exhibiting a longer life span with 30 or more passages before undergoing senescence. This may be related to WT being embryonal tumors with a strong differentiation potential that may prevail in vitro. Telomeres progressively shorten with cultivation, but their length does not predict lifespan. hTERT transfection may partly allow establishment of immortalized lines, because 2/7 cultures avoid senescence even in later passages. Importantly, these cells can be efficiently manipulated by transfection, making them a useful model system for in vitro testing.

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CITED1 Expression in Wilms' Tumor and Embryonic Kidney

Cited by 34 publications

References 40 publications

FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development

FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development

Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators

Characterization of primary wilms tumor cultures as an in vitro model

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