Impairment of developmental stem cell-mediated striatal neurogenesis and pluripotency genes in a knock-in model of Huntington's disease

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. development ͉ huntingtin ͉ medium spiny neurons ͉ neurodegeneration

Extensive changes in DNA methylation are associated with expression of mutant huntingtin

“…In particular, mice heterozygous for a Sox2 knockout exhibited epileptic and neurodegenerative phenotypes (29,30) and SOX2 mutations in humans are associated with neurological phenotypes including seizures (31). In addition, huntingtin knockin mice show altered levels of SOX2 protein and impaired striatal neurogenesis during brain maturation (32). In PC12 cells, AP-1 transcription factors were shown to govern the choice between neuronal differentiation and apoptosis (33).…”

MicroRNA-9 Regulates Neurogenesis in Mouse Telencephalon by Targeting Multiple Transcription Factors

“…Finally, defects in subpallial development in the miR-9-2/3 double mutant are reminiscent of mutant mice in which exon 1 of huntingtin (Htt) was replaced with a human mutant Htt exon 1; progenitor proliferation is enhanced, and differentiation suppressed, in the striatum (Molero et al, 2009). Huntington's disease is a neurogenic disorder associated with dysfunction and degeneration of mainly medial spiny neurons of the striatum, having a midlife onset.…”

“…Huntington's disease is a neurogenic disorder associated with dysfunction and degeneration of mainly medial spiny neurons of the striatum, having a midlife onset. However, the nexus of Huntington's disease might occur at an earlier time in the specification of the neurons (Molero et al, 2009). Nuclear localization of REST by Htt mutation with an expanded polyglutamate stretch is one putative molecular mechanism underlying Huntington's disease pathogenesis (Zuccato et al, 2003).…”

“…In the subpallium, lateral (LGE) and medial (MGE) ganglionic eminences generate distinct nuclei, including the striatum and the globus pallidus, respectively. The proliferation/differentiation of the subpallial progenitor cells are regulated by Mash1, Dlx1/2/5/6, Nkx2.1, and Gsh2 (Anderson et al, 1997;Horton et al, 1999;Sussel et al, 1999;Toresson et al, 2000;Yun et al, 2001;Flames et al, 2007;Molero et al, 2009). …”

REST and CoREST are transcriptional and epigenetic regulators of seminal neural fate decisions

“…85 These observations suggest that CoREST may preferentially promote NSC maintenance and fate restriction compared to REST and that specific core pluripotency genes may have distinct and previously unanticipated roles in early neural development. 86 Further, we performed REST and CoREST knockdown experiments utilizing NSC clonal expansion and differentiation assays to examine their roles in mediating neural cell fate decisions. These studies revealed that REST ablation impedes neurogenesis, consistent with previous studies, 53,82 whereas CoREST ablation significantly impedes NSC maintenance and altered neural fate restriction, consistent with distinct roles for CoREST in multi-lineage potential and early neural fate decisions.…”