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.
"In order to identify transcription factors that would favor the MSN fate, we transduced human postnatal fibroblasts with lentivirus to express miR-9/9*-124 and sixteen selected transcription factors individually and examined by immunostaining the number of MAP2-positive cells that were also positive for the neurotransmitter GABA and the dopamine-and cAMP-regulated neuronal phosphoprotein (DARPP-32), a well-documented marker of MSNs (Arlotta et al., 2008; Lobo et al., 2006; Ouimet and Greengard , 1990) (Figures 1A and S3). BCL11B (also known as CTIP2), a transcription factor critical for the differentiation of MSNs in vivo (Arlotta et al., 2008), was the only factor tested with miR-9/9*- 124 to yield DARPP-32-positive neurons (Figure 1A). Furthermore, when miR-9/9*-124 were combined with DLX1 and DLX2, previously shown to be important for terminal differentiation of MSNs (Anderson et al., 1997), we detected a large percentage of GABAergic neurons (72.3% of MAP2-positive cells) (Figure 1A). "
[Show abstract][Hide abstract] ABSTRACT: The promise of using reprogrammed human neurons for disease modeling and regenerative medicine relies on the ability to induce patient-derived neurons with high efficiency and subtype specificity. We have previously shown that ectopic expression of brain-enriched microRNAs (miRNAs), miR-9/9(∗) and miR-124 (miR-9/9(∗)-124), promoted direct conversion of human fibroblasts into neurons. Here we show that coexpression of miR-9/9(∗)-124 with transcription factors enriched in the developing striatum, BCL11B (also known as CTIP2), DLX1, DLX2, and MYT1L, can guide the conversion of human postnatal and adult fibroblasts into an enriched population of neurons analogous to striatal medium spiny neurons (MSNs). When transplanted in the mouse brain, the reprogrammed human cells persisted in situ for over 6 months, exhibited membrane properties equivalent to native MSNs, and extended projections to the anatomical targets of MSNs. These findings highlight the potential of exploiting the synergism between miR-9/9(∗)-124 and transcription factors to generate specific neuronal subtypes.
"CTIP2) is a transcription factor that has been described to be a key gene for differentiation of medium sized spiny neurons in the striatum. Since MSN represent ∼95% of the neurons in the striatum, Bcl11b likely possesses a central role that determines the architecture and organization of the striatum, and as such its function is likely crucial in HD (Arlotta et al., 2008). Bcl11b mRNA levels are reduced in the HD striatum. "
[Show abstract][Hide abstract] ABSTRACT: HD is caused by a mutation in the huntingtin gene that consists in a CAG repeat expansion translated into an abnormal poly-glutamine (polyQ) tract in the huntingtin (Htt) protein. The most striking neuropathological finding in HD is the atrophy of the striatum. The regional expression of mutant Htt (mHtt) is ubiquitous in the brain and cannot explain by itself the preferential vulnerability of the striatum in HD. mHtt has been shown to produce an early defect in transcription, through direct alteration of the function of key regulators of transcription and in addition, more indirectly, as a result of compensatory responses to cellular stress. In this review, we focus on gene products that are preferentially expressed in the striatum and have down- or up-regulated expression in HD and, as such, may play a crucial role in the susceptibility of the striatum to mHtt. Many of these striatal gene products are for a vast majority down-regulated and more rarely increased in HD. Recent research shows that some of these striatal markers have a pro-survival/neuroprotective role in neurons (e.g., MSK1, A2A, and CB1 receptors) whereas others enhance the susceptibility of striatal neurons to mHtt (e.g., Rhes, RGS2, D2 receptors). The down-regulation of these latter proteins may be considered as a potential self-defense mechanism to slow degeneration. For a majority of the striatal gene products that have been identified so far, their function in the striatum is unknown and their modifying effects on mHtt toxicity remain to be experimentally addressed. Focusing on these striatal markers may contribute to a better understanding of HD pathogenesis, and possibly the identification of novel therapeutic targets.
"Furthermore, we demonstrate that the expression of phosphorylated DARPP-32 (at position Thr34) is blunted in HPRT-deficient striatal cell lines relative to control in response dopamine receptor 1 agonist SKF38393 (Figure 3E); Paradoxically phosphorylated DARPP-32 (Thr34) is increased in the striatum of adult HPRTKO (Figure 3F). We elected to study DARPP-32 expression and signaling, since previous studies indicate DARPP-32 is severely blunted in Bcl11b knockout mice . DARPP-32 is a striatally-enriched phosphoprotein and is central to the neurotransmission of the striatum . "
[Show abstract][Hide abstract] ABSTRACT: Lesch-Nyhan Syndrome (LNS) is a neurodevelopmental disorder caused by mutations in the gene encoding the purine metabolic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). This syndrome is characterized by an array of severe neurological impairments that in part originate from striatal dysfunctions. However, the molecular and cellular mechanisms underlying these dysfunctions remain largely unidentified. In this report, we demonstrate that HPRT-deficiency causes dysregulated expression of key genes essential for striatal patterning, most notably the striatally-enriched transcription factor B-cell leukemia 11b (Bcl11b). The data also reveal that the down-regulated expression of Bcl11b in HPRT-deficient immortalized mouse striatal (STHdh) neural stem cells is accompanied by aberrant expression of some of its transcriptional partners and other striatally-enriched genes, including the gene encoding dopamine- and cAMP-regulated phosphoprotein 32, (DARPP-32). Furthermore, we demonstrate that components of the BDNF/TrkB signaling, a known activator of DARPP-32 striatal expression and effector of Bcl11b transcriptional activation are markedly increased in HPRT-deficient cells and in the striatum of HPRT knockout mouse. Consequently, the HPRT-deficient cells display superior protection against reactive oxygen species (ROS)-mediated cell death upon exposure to hydrogen peroxide. These findings suggest that the purine metabolic defect caused by HPRT-deficiency, while it may provide neuroprotection to striatal neurons, affects key genes and signaling pathways that may underlie the neuropathogenesis of LNS.
PLoS ONE 05/2014; 9(5):e96575. DOI:10.1371/journal.pone.0096575 · 3.23 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.