IPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth

Matthew E. Doers, Michael T. Musser, Robert Nichol, Erich R. Berndt, Mei Baker, Timothy M. Gomez, Su Chun Zhang, Leonard J Abbeduto, Anita Bhattacharyya

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and is closely linked with autism. The genetic basis of FXS is an expansion of CGG repeats in the 5′-untranslated region of the FMR1 gene on the X chromosome leading to the loss of expression of the fragile X mental retardation protein (FMRP). The cause of FXS has been known for over 20 years, yet the full molecular and cellular consequences of this mutation remain unclear. Although mouse and fly models have provided significant understanding of this disorder and its effects on the central nervous system, insight from human studies is limited. We have created human induced pluripotent stem cell (iPSC) lines from fibroblasts obtained from individuals with FXS to enable in vitro modeling of the human disease. Three young boys with FXS who came from a well-characterized cohort representative of the range of affectedness typical for the syndrome were recruited to aid in linking cellular and behavioral phenotypes. The FMR1 mutation is preserved during the reprogramming of patient fibroblasts to iPSCs. Mosaicism of the CGG repeat length in one of the patient's fibroblasts allowed for the generation of isogenic lines with differing CGG repeat lengths from the same patient. FXS forebrain neurons were differentiated from these iPSCs and display defective neurite initiation and extension. These cells provide a well-characterized resource to examine potential neuronal deficits caused by FXS as well as the function of FMRP in human neurons.

Original languageEnglish (US)
Pages (from-to)1777-1787
Number of pages11
JournalStem Cells and Development
Volume23
Issue number15
DOIs
StatePublished - Aug 1 2014

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Fragile X Syndrome
Prosencephalon
Neurons
Fragile X Mental Retardation Protein
Fibroblasts
Induced Pluripotent Stem Cells
X-Linked Genes
Mutation
Mosaicism
5' Untranslated Regions
Neurites
Autistic Disorder
Neuronal Outgrowth
Diptera
Intellectual Disability
Central Nervous System
Phenotype
Cell Line

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Hematology

Cite this

Doers, M. E., Musser, M. T., Nichol, R., Berndt, E. R., Baker, M., Gomez, T. M., ... Bhattacharyya, A. (2014). IPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth. Stem Cells and Development, 23(15), 1777-1787. https://doi.org/10.1089/scd.2014.0030

IPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth. / Doers, Matthew E.; Musser, Michael T.; Nichol, Robert; Berndt, Erich R.; Baker, Mei; Gomez, Timothy M.; Zhang, Su Chun; Abbeduto, Leonard J; Bhattacharyya, Anita.

In: Stem Cells and Development, Vol. 23, No. 15, 01.08.2014, p. 1777-1787.

Research output: Contribution to journalArticle

Doers, ME, Musser, MT, Nichol, R, Berndt, ER, Baker, M, Gomez, TM, Zhang, SC, Abbeduto, LJ & Bhattacharyya, A 2014, 'IPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth', Stem Cells and Development, vol. 23, no. 15, pp. 1777-1787. https://doi.org/10.1089/scd.2014.0030
Doers, Matthew E. ; Musser, Michael T. ; Nichol, Robert ; Berndt, Erich R. ; Baker, Mei ; Gomez, Timothy M. ; Zhang, Su Chun ; Abbeduto, Leonard J ; Bhattacharyya, Anita. / IPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth. In: Stem Cells and Development. 2014 ; Vol. 23, No. 15. pp. 1777-1787.
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