Premutation CGG-repeat expansion of the Fmr1 gene impairs mouse neocortical development

Christopher L. Cunningham, Veronica Martinez-Cerdeno, Eliecer Navarro Porras, Anish N. Prakash, James M Angelastro, Rob Willemsen, Paul J Hagerman, Isaac N Pessah, Robert F Berman, Stephen C Noctor

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Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder caused by a premutation CGG-trinucleotide repeat expansion (55-200 CGG repeats) within the 5′-untranslated region of the FMR1 gene. Although FXTAS generally affects premutation carriers over 50 years of age, cognitive and psychological symptoms can appear in carriers during childhood, suggesting that the FMR1 premutation affects brain function early in life. Recent work with cultured hippocampal neurons from a premutation (Fmr1 CGG knock-in) mouse model revealed impaired development of early postnatal neurons, consistent with the developmental clinical involvement of premutation carriers. In the current work, we show that the presence of premutation CGG-repeat expansions in the mouse Fmr1 gene alters embryonic neocortical development. Specifically, embryonic premutation mice display migration defects in the neocortex and altered expression of neuronal lineage markers. The current data demonstrate that premutation alleles of the Fmr1 gene are associated with defects in developmental programs operating during prenatal stages of brain formation and provide further evidence that the FMR1 premutation has a neurodevelopmental component.

Original languageEnglish (US)
Pages (from-to)64-79
Number of pages16
JournalHuman Molecular Genetics
Volume20
Issue number1
DOIs
StatePublished - Jan 2011

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Trinucleotide Repeat Expansion
Genes
Neurons
Neurobehavioral Manifestations
5' Untranslated Regions
Neocortex
Brain
Neurodegenerative Diseases
Embryonic Development
Alleles
Psychology
Fragile X Tremor Ataxia Syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Premutation CGG-repeat expansion of the Fmr1 gene impairs mouse neocortical development. / Cunningham, Christopher L.; Martinez-Cerdeno, Veronica; Porras, Eliecer Navarro; Prakash, Anish N.; Angelastro, James M; Willemsen, Rob; Hagerman, Paul J; Pessah, Isaac N; Berman, Robert F; Noctor, Stephen C.

In: Human Molecular Genetics, Vol. 20, No. 1, 01.2011, p. 64-79.

Research output: Contribution to journalArticle

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