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.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autistic Disorder / genetics
  • Cell Line
  • Cell Proliferation
  • Cerebrum / pathology*
  • Chromosome Deletion*
  • Chromosomes, Human, Pair 17 / genetics*
  • Dendrites / metabolism
  • Dendrites / pathology
  • Enzyme Activation
  • Gene Deletion
  • Genes, Neurofibromatosis 1
  • Humans
  • Induced Pluripotent Stem Cells / pathology*
  • Models, Biological*
  • Mutation / genetics
  • Neurogenesis / genetics*
  • Organoids / pathology*
  • Receptors, Cytokine / metabolism*
  • Signal Transduction
  • ras Proteins / metabolism
  • rhoA GTP-Binding Protein / metabolism


  • CRLF3 protein, human
  • Receptors, Cytokine
  • ras Proteins
  • rhoA GTP-Binding Protein