@article{528e1526ca83498d9347540232a860c3,
title = "Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis",
abstract = "Neurodevelopmental disorders are often caused by chromosomal microdeletions comprising numerous contiguous genes. A subset of neurofibromatosis type 1 (NF1) patients with severe developmental delays and intellectual disability harbors such a microdeletion event on chromosome 17q11.2, involving the NF1 gene and flanking regions (NF1 total gene deletion [NF1-TGD]). Using patient-derived human induced pluripotent stem cell (hiPSC)-forebrain cerebral organoids (hCOs), we identify both neural stem cell (NSC) proliferation and neuronal maturation abnormalities in NF1-TGD hCOs. While increased NSC proliferation results from decreased NF1/RAS regulation, the neuronal differentiation, survival, and maturation defects are caused by reduced cytokine receptor-like factor 3 (CRLF3) expression and impaired RhoA signaling. Furthermore, we demonstrate a higher autistic trait burden in NF1 patients harboring a deleterious germline mutation in the CRLF3 gene (c.1166T>C, p.Leu389Pro). Collectively, these findings identify a causative gene within the NF1-TGD locus responsible for hCO neuronal abnormalities and autism in children with NF1.",
keywords = "CRLF3, RAS, autism, brain development, cerebral organoids, human induced pluripotent stem cells, intellectual disability, microdeletion, neurofibromatosis type 1, neurons",
author = "Wegscheid, {Michelle L.} and Corina Anastasaki and Hartigan, {Kelly A.} and Cobb, {Olivia M.} and Papke, {Jason B.} and Traber, {Jennifer N.} and Morris, {Stephanie M.} and Gutmann, {David H.}",
note = "Funding Information: We thank Dr. Matthew B. Harms and Dr. Fumihiko Urano (Washington University, St. Louis, MO) for providing neurologically normal control patient-derived hiPSC lines. This work was supported by a Young Investigator{\textquoteright}s Award grant from the Children's Tumor Foundation ( 2018-01-003 to M.L.W.) and a Research Program Award grant from the National Institutes of Health ( 1-R35-NS07211-01 to D.H.G.). The GeiC facility at WUSM engineered the hiPSCs and is subsidized by NCI Cancer Center Support Grant P30-CA091842 . Funding Information: We thank Dr. Matthew B. Harms and Dr. Fumihiko Urano (Washington University, St. Louis, MO) for providing neurologically normal control patient-derived hiPSC lines. This work was supported by a Young Investigator's Award grant from the Children's Tumor Foundation (2018-01-003 to M.L.W.) and a Research Program Award grant from the National Institutes of Health (1-R35-NS07211-01 to D.H.G.). The GeiC facility at WUSM engineered the hiPSCs and is subsidized by NCI Cancer Center Support Grant P30-CA091842. M.L.W. and D.H.G. designed the experiments. M.L.W. K.A.H. O.M.C. C.A. S.M.M. and J.B.P. conducted the experiments and/or analyzed the data. S.M.M. and J.N.T. collected patient specimens. The manuscript was assembled by M.L.W. and D.H.G. D.H.G. was responsible for the final production of the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = jul,
day = "6",
doi = "10.1016/j.celrep.2021.109315",
language = "English",
volume = "36",
journal = "Cell Reports",
issn = "2211-1247",
number = "1",
}