Cells of Origin in the Embryonic Nerve Roots for NF1-Associated Plexiform Neurofibroma

Chen, Zhi Guo; Liu, Chiachi; Patel, Aditi; Liao, Chung Ping; Wang, Yong; Le, Lu Q.

doi:10.1016/j.ccell.2014.09.009

Cited by 87 publications

(89 citation statements)

References 51 publications

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“…Unexpectedly, plexiform neurofibromas can be induced even in adult mice, although in one model these are rare 116,117 . Unfortunately, this result does not resolve the uncertainty around the plexiform neurofibroma cell of origin, as adult mouse dorsal root ganglia and dorsal roots contain stem-like cells, mature Schwann cells and satellite cells, all of which have been proposed as possible neurofibroma-initiating cells 115–118,120 . Epidermal growth factor receptor (EGFR)-expressing Schwann cell precursor-like cells are present in mouse and human neurofibromas, and form neurofibroma-like lesions under the skin 120 or in peripheral nerves 121 of immunocompromised mice.…”

Section: Nf1 Tumorigenesis and Tumour Cells Of Originmentioning

confidence: 91%

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

2015

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Neurofibromatosis type 1 (NF1) is a common genetic disorder that predisposes affected individuals to tumours. The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin and is one of several genes that (when mutant) affect RAS–MAPK signalling, causing related diseases collectively known as RASopathies. Several RASopathies, beyond NF1, are cancer predisposition syndromes. Somatic NF1 mutations also occur in 5–10% of human sporadic cancers and may contribute to resistance to therapy. To highlight areas for investigation in RASopathies and sporadic tumours with NF1 mutations, we summarize current knowledge of NF1 disease, the NF1 gene and neurofibromin, neurofibromin signalling pathways and recent developments in NF1 therapeutics.

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Section: Nf1 Tumorigenesis and Tumour Cells Of Originmentioning

confidence: 91%

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

2015

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“…Neurofibromas may develop from SCs or SCPs, because inactivation of Nf1 at the SCP stage or in adult mice results in neurofibroma formation (Chen et al, 2014; Wu et al, 2008; Zhu et al, 2002). NF1 encodes the RasGAP protein neurofibromin, and Ras signaling is elevated in neurofibroma SCs (Cichowski and Jacks, 2001).…”

Section: Introductionmentioning

confidence: 99%

Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation

Keng

Patmore

et al. 2016

Cell Reports

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Summary To identify genes and signaling pathways that initiate Neurofibromatosis type 1 (Nf1) neurofibroma, we used unbiased insertional mutagenesis screening, mouse models, and molecular analyses. We mapped an Nf1-Stat3-Arid1b/β-catenin pathway which becomes active in the context of Nf1 loss. Genetic deletion of Stat3 in Schwann cells progenitors (SCPs) and Schwann cells (SCs) prevents neurofibroma formation, decreasing SCP self-renewal and β-catenin activity. β-catenin expression rescues effects of Stat3 loss in SCPs. Importantly, P-STAT3 and β-catenin expression correlate in human neurofibromas. Mechanistically, P-Stat3 represses Gsk3β and the SWI/SNF gene Arid1b, to increase β-catenin. Knock-down of Arid1b or Gsk3β in Stat3fl/f;Nf1fl/fl;DhhCre SCPs rescues neurofibroma formation after in vivo transplantation. Stat3 represses Arid1b through histone modification in a Brg1 dependent manner, indicating that epigenetic modification plays a role in early tumorigenesis. Our data map a neural tumorigenesis pathway, and support testing JAK/STAT and Wnt/β-catenin pathway inhibitors in neurofibroma therapeutic trials.

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“…K14-Scf (Kunisada et al 1998a) was kindly provided by Dr. John Harris (University of Massachusetts Medical School). Krox20Cre , DhhCre (Skucas et al 2013), PLPCre ERT2 (Leone et al 2003), CMVCre ERT (Hayashi and McMahon 2002), R26-LacZ, and R26-YFP were described previously (Le et al 2009;Chen et al 2014). …”

Section: Micementioning

confidence: 99%

Identification of hair shaft progenitors that create a niche for hair pigmentation

et al. 2017

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Hair differentiates from follicle stem cells through progenitor cells in the matrix. In contrast to stem cells in the bulge, the identities of the progenitors and the mechanisms by which they regulate hair shaft components are poorly understood. Hair is also pigmented by melanocytes in the follicle. However, the niche that regulates follicular melanocytes is not well characterized. Here, we report the identification of hair shaft progenitors in the matrix that are differentiated from follicular epithelial cells expressing transcription factor KROX20. Depletion of Krox20 lineage cells results in arrest of hair growth, confirming the critical role of KROX20 + cells as antecedents of structural cells found in hair. Expression of stem cell factor (SCF) by these cells is necessary for the maintenance of differentiated melanocytes and for hair pigmentation. Our findings reveal the identities of hair matrix progenitors that regulate hair growth and pigmentation, partly by creating an SCF-dependent niche for follicular melanocytes.

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Cells of Origin in the Embryonic Nerve Roots for NF1-Associated Plexiform Neurofibroma

Cited by 87 publications

References 51 publications

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation

Identification of hair shaft progenitors that create a niche for hair pigmentation

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