Human iPSC-Derived Neurons and Cerebral Organoids Establish Differential Effects of Germline NF1 Gene Mutations. Stem Cell Reports 2020 Apr 14;14(4):541-550
Date
04/04/2020Pubmed ID
32243842Pubmed Central ID
PMC7160375DOI
10.1016/j.stemcr.2020.03.007Scopus ID
2-s2.0-85082754501 (requires institutional sign-in at Scopus site) 47 CitationsAbstract
Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by a spectrum of distinct germline NF1 gene mutations, traditionally viewed as equivalent loss-of-function alleles. To specifically address the issue of mutational equivalency in a disease with considerable clinical heterogeneity, we engineered seven isogenic human induced pluripotent stem cell lines, each with a different NF1 patient NF1 mutation, to identify potential differential effects of NF1 mutations on human central nervous system cells and tissues. Although all mutations increased proliferation and RAS activity in 2D neural progenitor cells (NPCs) and astrocytes, we observed striking differences between NF1 mutations on 2D NPC dopamine levels, and 3D NPC proliferation, apoptosis, and neuronal differentiation in developing cerebral organoids. Together, these findings demonstrate differential effects of NF1 gene mutations at the cellular and tissue levels, suggesting that the germline NF1 gene mutation is one factor that underlies clinical variability.
Author List
Anastasaki C, Wegscheid ML, Hartigan K, Papke JB, Kopp ND, Chen J, Cobb O, Dougherty JD, Gutmann DHAuthor
Nathan Kopp PhD Assistant Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Astrocytes
Brain
Cell Differentiation
Cell Line
Cell Proliferation
Genes, Neurofibromatosis 1
Humans
Induced Pluripotent Stem Cells
Mice, Mutant Strains
Mutation
Neurogenesis
Neurons
Organoids
ras Proteins
