Am J Stem Cell 2012;1(2):154-162

Original Article
Gene expression changes in the MAPK pathway in both Fragile X and Down
syndrome human neural progenitor cells

Erin L McMillan, Allison L Kamps, Samuel S Lake, Clive N Svendsen, Anita Bhattacharyya

Stem Cell Research Program, Waisman Center, University of Wisconsin-Madison, WI 53705, USA; Regenerative Medicine Institute,
Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA

Received May 1, 2012; accepted May 28, 2012; Epub June 3, 2012; Published June 30, 2012

Abstract: The two most common genetic developmental disorders that cause intellectual disability are Down syndrome (DS) and Fragile
X syndrome (FXS). Although the genetics and behavioral hallmarks of these two disorders are distinct, common underlying defects in
neural development may lead to the cognitive impairment characteristic of both. Human neural progenitor cells (hNPCs) enable the study
of prenatal human brain development in these developmental disorders. We therefore tested whether there are common affected
molecular pathways in FXS and DS hNPCs that may be indicators of the fundamental developmental causes of intellectual disability.
Comparison of gene expression data from FXS and DS (disorder group) hNPCs to unaffected hNPCs indicated genes in specific signal
transduction cascades are dysregulated. Importantly, altered expression of genes in these signaling pathways did not emerge when the
two disorder hNPCs were analyzed separately. Specifically, genes in the mitogen-activated protein kinases (MAPK/ERK) and calcium
signaling pathways are mis-expressed in disorder hNPCs. These results suggest that DS and FXS hNPCs do not communicate or
respond appropriately to extracellular cues during neural development. These results validate the use of hNPCs as a tool to assess
complex cell functions during neural development and suggest that defects in the pathways identified could have profound effects on
how neural progenitor cells survive, proliferate and differentiate, thereby leading to intellectual disability. (AJSC1205001).

Keywords: Down syndrome, Fragile X syndrome, developmental disorders, intellectual disability, mental impairment, neurogenesis,
neural progenitor cells, human, transcriptional analysis, MAPK

Address all correspondence to:
Dr. Anita Bhattacharyya
Stem Cell Research Program
Waisman Center, University of Wisconsin
Madison, WI 53705, USA.
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