Ctip2 controls the differentiation of medium spiny neurons and the establishment of the cellular architecture of the striatum
ABSTRACT Striatal medium spiny neurons (MSN) are critically involved in motor control, and their degeneration is a principal component of Huntington's disease. We find that the transcription factor Ctip2 (also known as Bcl11b) is central to MSN differentiation and striatal development. Within the striatum, it is expressed by all MSN, although it is excluded from essentially all striatal interneurons. In the absence of Ctip2, MSN do not fully differentiate, as demonstrated by dramatically reduced expression of a large number of MSN markers, including DARPP-32, FOXP1, Chrm4, Reelin, MOR1 (mu-opioid receptor 1), glutamate receptor 1, and Plexin-D1. Furthermore, MSN fail to aggregate into patches, resulting in severely disrupted patch-matrix organization within the striatum. Finally, heterotopic cellular aggregates invade the Ctip2-/- striatum, suggesting a failure by MSN to repel these cells in the absence of Ctip2. This is associated with abnormal dopaminergic innervation of the mutant striatum and dramatic changes in gene expression, including dysregulation of molecules involved in cellular repulsion. Together, these data indicate that Ctip2 is a critical regulator of MSN differentiation, striatal patch development, and the establishment of the cellular architecture of the striatum.
SourceAvailable from: Amina M Bagher[Show abstract] [Hide abstract]
ABSTRACT: The endocannabinoid system (ECS) and the dopaminergic system (DAS) are two major regulators of basal ganglia function. During Huntington's disease (HD) pathogenesis, the expression of genes in both the ECS and DAS is dysregulated. The purpose of this study was to determine the changes that were consistently observed in the ECS and DAS during HD progression in the central nervous system (CNS) and in the periphery in different models of HD and human HD tissue. To do this, we conducted a meta-analysis of differential gene expression in the ECS and DAS using publicly available microarray data. The consolidated data were summarized as observed changes in gene expression (OCGE) using a weighted sum for each gene. In addition, consolidated data were compared to previously published studies that were not available in the gene expression omnibus (GEO) database. The resulting data confirm gene expression changes observed using different approaches and provide novel insights into the consistency between changes observed in human tissue and various models, as well as disease stage- and tissue-specific transcriptional dysregulation in HD. The major implication of the systems-wide data presented here is that therapeutic strategies targeting the ECS or DAS must consider the dynamic changes in gene expression over time and in different body areas, which occur during HD progression and the interconnectedness of the two systems.02/2015; 3(1). DOI:10.1002/prp2.104
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ABSTRACT: The efficient generation of striatal neurons from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) is fundamental for realising their promise in disease modelling, pharmaceutical drug screening and cell therapy for Huntington's disease. GABAergic medium-sized spiny neurons (MSNs) are the principal projection neurons of the striatum and specifically degenerate in the early phase of Huntington's disease. Here we report that activin A induces lateral ganglionic eminence (LGE) characteristics in nascent neural progenitors derived from hESCs and hiPSCs in a sonic hedgehog-independent manner. Correct specification of striatal phenotype was further demonstrated by the induction of the striatal transcription factors CTIP2, GSX2 and FOXP2. Crucially, these human LGE progenitors readily differentiate into postmitotic neurons expressing the striatal projection neuron signature marker DARPP32, both in culture and following transplantation in the adult striatum in a rat model of Huntington's disease. Activin-induced neurons also exhibit appropriate striatal-like electrophysiology in vitro. Together, our findings demonstrate a novel route for efficient differentiation of GABAergic striatal MSNs from human pluripotent stem cells. © 2015. Published by The Company of Biologists Ltd.Development 04/2015; 142(7-7):1375-1386. DOI:10.1242/dev.117093 · 6.27 Impact Factor
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ABSTRACT: The mature striatum is divided into a labyrinthine system of striosomes embedded in a surrounding matrix compartment. We pulse-labeled striosomal cells (S cells) and matrix cells (M cells) in cats with (3) H-thymidine and followed their distributions during fetal and post-natal development. We identified three maturational phases in S-cell distributions. The early phase (sampled at E27-E35 following E24-E28 (3) H-thymidine) was characterized by a transient medial accumulation of synchronously generated S cells within the caudate nucleus adjoining the ganglionic eminence, potentially a waiting compartment. Band-like arrangements of synchronously generated S cells then formed beyond this medial band. During the second phase (sampled at E38-E45), the loosely banded S-cell distributions were transformed into clustered arrangements typical of developing striosomes. In the third phase (sampled from E52 into the postnatal period), these matured into the typical mature striosomal architecture. At adulthood, gentle mediolateral birthdate-gradients in S cells were still evident, but M cells, produced over mid to late prenatal ages, became broadly distributed, without apparent gradients or banding arrangements. These findings suggest that the maturational histories of the striosomal and matrix neurons are influenced by their generation times and local environments, and that future S cells have transient, non-striosomal distributions prior to their aggregation into striosomal clusters, including a putative waiting compartment. Further, the eventual patterning of the striosomal compartment reflects an outside-in, band-like gradient patterns of settling of synchronously generated S cells, patterns that could be related both to neural processing in the mature striatum and to patterns of vulnerability of striatal neurons. This article is protected by copyright. All rights reserved. Copyright © 2014 Wiley Periodicals, Inc., A Wiley Company.The Journal of Comparative Neurology 04/2015; 523(6). DOI:10.1002/cne.23725 · 3.51 Impact Factor