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.

Download full-text


Available from: Jeffrey Macklis, Nov 19, 2015
26 Reads
  • Source
    • "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.
    Neuron 10/2014; 84(2):311-23. DOI:10.1016/j.neuron.2014.10.016 · 15.05 Impact Factor
  • Source
    • "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.
    Frontiers in Cellular Neuroscience 09/2014; 8:295. DOI:10.3389/fncel.2014.00295 · 4.29 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Histological and morphological studies indicate that approximately 5% of striatal neurons are cholinergic or γ-aminobutyric acidergic (GABAergic) interneurons (gINs). However, the number of striatal neurons expressing known interneuron markers is too small to account for the entire interneuron population. We therefore studied the serotonin (5HT) receptor 3a-enhanced green fluorescent protein (5HT3aEGFP) mouse, in which we found that a large number of striatal gINs are labeled. Roughly 20% of 5HT3aEGFP-positive cells co-express parvalbumin and exhibit fast-spiking (FS) electrophysiological properties. However, the majority of labeled neurons do not overlap with known molecular interneuron markers. Intrinsic electrical properties reveal at least 2 distinct novel subtypes: a late-spiking (LS) neuropeptide-Y (NPY)-negative neurogliaform (NGF) interneuron, and a large heterogeneous population with several features resembling low-threshold-spiking (LTS) interneurons that do not express somatostatin, NPY, or neuronal nitric oxide synthase. Although the 5HT3aEGFP NGF and LTS-like interneurons have electrophysiological properties similar to previously described populations, they are pharmacologically distinct. In direct contrast to previously described NPY+ LTS and NGF cells, LTS-like 5HT3aEGFP cells show robust responses to nicotine administration, while the 5HT3aEGFP NGF cell type shows little or no response. By constructing a molecular map of the overlap between these novel populations and existing interneuron populations, we are able to reconcile the morphological and molecular estimates of striatal interneuron numbers.
    Cerebral Cortex 08/2014; DOI:10.1093/cercor/bhu179 · 8.67 Impact Factor
Show more