1. Academic Validation
  2. Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis

Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis

  • Cell Rep. 2021 Jul 6;36(1):109315. doi: 10.1016/j.celrep.2021.109315.
Michelle L Wegscheid 1 Corina Anastasaki 1 Kelly A Hartigan 1 Olivia M Cobb 1 Jason B Papke 1 Jennifer N Traber 1 Stephanie M Morris 1 David H Gutmann 2
Affiliations

Affiliations

  • 1 Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 2 Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: gutmannd@wustl.edu.
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.

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  • HY-101295
    99.16%, Ras Inhibitor
    Ras