Ctip2 Controls the Differentiation of Medium Spiny Neurons and the Establishment of the Cellular Architecture of the Striatum

Massachusetts General Hospital-Harvard Medical School Center for Nervous System Repair, Nayef Al-Rodhan Laboratories, Department of Neurosurgery, Boston, Massachusetts 02114, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2008; 28(3):622-32. DOI: 10.1523/JNEUROSCI.2986-07.2008
Source: PubMed


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.

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Available from: Jeffrey Macklis, Nov 19, 2015
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    • "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). "
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    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.
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    • "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. "
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    • "All EGFP + cells were GABAergic (100%, n = 4 animals, >100 cells per animal), as shown by in situ hybridization for Gad1 combined with immunohistochemistry against EGFP (Fig. 1B). While 6.84 ± 1.58% (n = 7 animals) of EGFP + cells were labeled by the MSN marker Ctip2 (Arlotta et al. 2008), double immunofluorescence revealed no overlap with DARPP-32, another MSN marker, in EGFP-expressing cells (Fig. 1B,C). Furthermore, the EGFP/Ctip2 double-positive neurons never exhibited spiny dendrites (Supplementary Fig. 1), arguing that Ctip2 is not specific to MSNs (n = 15 cells). "
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