Normal Neurogenesis but Abnormal Gene Expression in Human Fragile X Cortical Progenitor Cells

Stem Cells Dev. 2008 Feb;17(1):107-17. doi: 10.1089/scd.2007.0073.

Abstract

Human stem and progenitor cells offer an innovative way to study early events in development. An exciting new opportunity for these cells is their application to study the underlying developmental consequences of genetic diseases. Because many diseases, ranging from leukemias to developmental disorders, are caused by single-gene defects, stem and progenitor cells that carry disease-causing genetic mutations are invaluable in understanding and treating disease. We have characterized human neural progenitor (hNPCs) cells that carry a single-gene defect that leads to the neurodevelopmental disorder Fragile X syndrome (FX). A loss-of-function mutation in the FMR1 gene leads to subtle changes in neural development and subsequent mental impairment characteristic of FX. hNPCs were isolated from fetal cortex carrying the FMR1 mutation to determine whether aberrations occur in their proliferation and differentiation. As expected, FX hNPCs have reduced expression of the FMR1 gene product Fragile X mental retardation protein (FMRP), and this decrease is maintained in culture and following differentiation. In contrast to a previously published report, the proliferation of FX hNPCs and their differentiation into neurons is not different from unaffected controls. Although the early development of FX hNPCs is essentially normal, microarray analysis reveals novel changes in the expression of signal transduction genes in FX hNPCs. Therefore, hNPCs have intrinsic characteristics that can be investigated to further our understanding and potential treatment of developmental disorders such as FX.

Publication types

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

MeSH terms

  • Cell Differentiation
  • Cell Proliferation
  • Cerebral Cortex / embryology
  • Cerebral Cortex / pathology*
  • Fetal Stem Cells / pathology*
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Syndrome / genetics*
  • Fragile X Syndrome / pathology*
  • Humans
  • Mutation*
  • Neurons / cytology*

Substances

  • Fragile X Mental Retardation Protein