Dataset Information

Neurofibromatosis 1 mutation impairs human induced pluripotent stem cell-derived microglia function

ABSTRACT: Neurofibromatosis type 1 (NF1) is autosomal dominant condition caused by germline mutations in the NF1 gene on chromosome 17. Children with NF1 are prone to the development of multiple nervous system abnormalities, including autism and brain tumors, which could result from the effect of NF1 mutation on microglia function. Using Nf1-mutant mice, we previously identified impaired microglia process extension and phagocytosis resulting from defects in purinergic signaling. To determine whether these abnormalities are also observed in human microglia, we leveraged human induced pluripotent stem cell engineering to generate human microglia-like (hiMGL) cells harboring three different NF1 patient-derived NF1 gene mutations. Both NF1-mutant and isogenic control hiMGL cells express classical microglial markers and exhibit similar transcriptomes and cytokine/chemokine release profiles, NF1-mutant hiMGL cells have defects in P2X receptor activation, phagocytosis and motility. We conclude that NF1 mutation impairs some aspects of microglia function in humans, which could contribute to a subset of the neurological abnormalities seen in children with NF1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE203647 | GEO | 2023/12/14

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Neurofibromatosis Type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating effects of hyperactive Ras in NF1 tumors are unknown. Cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate Ras-Raf- MEK- extracellular signal-regulated protein kinase (ERK) signaling in both species. Nonetheless, activation of ERK was sustained in mouse and human neurofibromas and MPNST. PD0325901, a highly selective pharmacological inhibitor of MEK, was used to test whether sustained Ras-Raf-MEK-ERK signaling contributes to neurofibroma growth in the Nf1fl/fl;Dhh-cre mouse model or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in >80% of mice tested. PD0325901 also caused effects on tumor vasculature. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide strong rationale for testing MEK inhibitors in NF1 clinical trials. 83 microarrays: Mouse control (15), Mouse neurofibroma (15), Mouse MPNST (18); Human nerve (3), Human neurofibroma (26), Human MPNST (6) We used the same human tumor samples as in series GSE14038 (dNF, pNF and MPNST). However, instead of referencing gene expression changes to the normal human Schwann cell samples (NHSC) as we did in series GSE14038, we generated three (new) normal nerve samples (samples jan-N1-3) and referenced gene expression changes to those samples. Moreover, the analysis of series GSE14038 evaluated changes in expression between NHSC, benign tumor subtypes (dNF and pNF), and malignant tumors (MPNST), while our present submission evaluated changes between normal nerve, benign tumors (combined dNF and pNF),and malignant tumors (MPNST). The Series supplementary 'merged_data.txt' file contains the data for 9,891 transcripts that were statistically different in at least one of the two species and present in both mouse and human data sets.

Dataset Information

Neurofibromatosis 1 mutation impairs human induced pluripotent stem cell-derived microglia function

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets