Impairment of developmental stem cell-mediated striatal neurogenesis and pluripotency genes in a knock-in model of Huntington's disease
- 22 December 2009
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 106 (51), 21900-21905
- https://doi.org/10.1073/pnas.0912171106
Abstract
The pathogenesis of Huntington's disease (HD) remains elusive. The identification of increasingly early pathophysiological abnormalities in HD suggests the possibility that impairments of striatal medium spiny neuron (MSN) specification and maturation may underlie the etiology of HD. In fact, we demonstrate that HD knock-in (Hdh-Q111) mice exhibited delayed acquisition of early striatal cytoarchitecture with aberrant expression of progressive markers of MSN neurogenesis (Islet1, DARPP-32, mGluR1, and NeuN). Hdh-Q111 striatal progenitors also displayed delayed cell cycle exit between E13.5-15.5 (BrdU birth-dating) and an enhanced fraction of abnormal cycling cells in association with expansion of the pool of intermediate progenitors and over expression of the core pluripotency (PP) factor, Sox2. Clonal analysis further revealed that Hdh-Q111 neural stem cells (NSCs) displayed: impaired lineage restriction, reduced proliferative potential, enhanced late-stage self-renewal, and deregulated MSN subtype specification. Further, our analysis revealed that in addition to Sox2, the core PP factor, Nanog is expressed within the striatal generative and mantle regions, and in Hdh-Q111 embryos the fraction of Nanog-expressing MSN precursors was substantially increased. Moreover, compared to Hdh-Q18 embryos, the Hdh-Q111 striatal anlagen exhibited significantly higher levels of the essential PP cofactor, Stat3. These findings suggest that Sox2 and Nanog may play roles during a selective window of embryonic brain maturation, and alterations of these factors may, in part, be responsible for mediating the aberrant program of Hdh-Q111 striatal MSN specification and maturation. We propose that these HD-associated developmental abnormalities might compromise neuronal homeostasis and subsequently render MSNs more vulnerable to late life stressors.Keywords
This publication has 36 references indexed in Scilit:
- The transcriptional foundation of pluripotencyDevelopment, 2009
- Failure of neuronal homeostasis results in common neuropsychiatric phenotypesNature, 2008
- Identification of Pou5f1, Sox2, and Nanog downstream target genes with statistical confidence by applying a novel algorithm to time course microarray and genome-wide chromatin immunoprecipitation dataBMC Genomics, 2008
- In Vivo Fate Analysis Reveals the Multipotent and Self-Renewal Capacities of Sox2+ Neural Stem Cells in the Adult HippocampusCell Stem Cell, 2007
- A Progressive and Cell Non-Autonomous Increase in Striatal Neural Stem Cells in the Huntington's Disease R6/2 MouseJournal of Neuroscience, 2006
- Notch signaling coordinates the patterning of striatal compartmentsDevelopment, 2005
- Impaired learning-dependent cortical plasticity in Huntington's disease transgenic miceNeurobiology of Disease, 2004
- Striatal Neuron Differentiation from Neurosphere-Expanded Progenitors Depends onGsh2ExpressionJournal of Neuroscience, 2004
- Homotopic glial regulation of striatal projection neuron differentiationNeuroReport, 2003
- Homotopic glial regulation of striatal projection neuron differentiationNeuroReport, 2003