Mus musculus
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ABSTRACT:
PROVIDER: PRJNA103005 | ENA |
REPOSITORIES: ENA
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Project description:Striatal medium spiny neurons (MSN) are critically involved in motor control, and their degeneration is a principal component of Huntingtonâs 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, while 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, GluR1, 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. In order to investigate the molecular mechanisms that underlie Ctip2-dependent differentiation of MSN and that underlie the patch-matrix disorganization in the mutant striatum, we directly compared gene expression between wild type and mutant striatum at P0. Because CTIP2-expressing MSN constitute 90-95% of the neurons within the striatum, we reasoned that we should be able to detect changes in medium spiny neuron gene expression in Ctip2 null mutants. We microdissected out small regions of striatum at matched locations in wild type and Ctip2-/- mutant littermates at P0 and investigated gene expression with Affymetrix microarrays. We selected the 153 most significant genes and further analyzed them to identify a smaller set of genes of potentially high biological relevance. In order to verify the microarray data and define the distribution of the identified genes in the striatum, we performed in situ hybridization or immunohistochemistry for 12 selected genes: Plexin-D1, Ngef, Nectin-3, Kcnip2, Pcp4L1, Neto1, Basonuclin 2, Fidgetin, Semaphorin 3e, Secretagogin, Unc5d, and Neurotensin. We find that all these genes are either specifically downregulated (Plexin-D1, Ngef, Nectin-3 Kcnip2, Pcp4L1, Neto1), or upregulated (Basonuclin 2, Fidgetin, Semaphorin 3e, Secretagogin, Unc5d, Neurotensin), in the Ctip2-/- striatum, confirming and extending the microarray results. 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. Experiment Overall Design: Matched regions of striatum from wild type and Ctip2-/- mice were obtained via 500 µm diameter punch biopsies performed in the center of the developing striatum in acutely sectioned 300 µm coronal slices of the brain at postnatal day 0 (P0). Sections were matched rostro-caudally between wild type and null mutant tissue, and fiduciary landmarks were used to assure reproducible microdissection of comparable regions. RNA was extracted using the StrataPrep Total RNA Mini Kit (Stratagene, La Jolla, CA), and RNA quality was assayed using a bioanalyzer (Agilent Technologies, Paola Alto, CA). To ensure reproducibility and biological significance, microarrays were performed with RNA samples from three independent wild type, one heterozygote, and four Ctip2-/- mice (biological replicates). Microarray data were normalized using the RMA function within Bioconductor (Irizarry et al., 2003). Statistical significance of gene expression differences between wild type and knockout was determined using Statistical Analysis of Micrarrays (SAM) (Tusher et al., 2001). Using a SAM d-score cutoff of > 2 or < -2, we selected the 153 most significant genes and further analyzed them to identify a smaller set of genes of potentially high biological relevance.
2008-06-16 | E-GEOD-9330 | biostudies-arrayexpress
Project description: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, while 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, GluR1, 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. In order to investigate the molecular mechanisms that underlie Ctip2-dependent differentiation of MSN and that underlie the patch-matrix disorganization in the mutant striatum, we directly compared gene expression between wild type and mutant striatum at P0. Because CTIP2-expressing MSN constitute 90-95% of the neurons within the striatum, we reasoned that we should be able to detect changes in medium spiny neuron gene expression in Ctip2 null mutants. We microdissected out small regions of striatum at matched locations in wild type and Ctip2-/- mutant littermates at P0 and investigated gene expression with Affymetrix microarrays. We selected the 153 most significant genes and further analyzed them to identify a smaller set of genes of potentially high biological relevance. In order to verify the microarray data and define the distribution of the identified genes in the striatum, we performed in situ hybridization or immunohistochemistry for 12 selected genes: Plexin-D1, Ngef, Nectin-3, Kcnip2, Pcp4L1, Neto1, Basonuclin 2, Fidgetin, Semaphorin 3e, Secretagogin, Unc5d, and Neurotensin. We find that all these genes are either specifically downregulated (Plexin-D1, Ngef, Nectin-3 Kcnip2, Pcp4L1, Neto1), or upregulated (Basonuclin 2, Fidgetin, Semaphorin 3e, Secretagogin, Unc5d, Neurotensin), in the Ctip2-/- striatum, confirming and extending the microarray results. 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. Keywords: mutant analysis
2007-12-15 | GSE9330 | GEO
Project description:Purpose:To assess changes in gene expression profiles of single cell from the wild type littermate controls cortices in E13.5, E15.5 and P0, and conditional knockout Bcl11a (and Bcl11b) at cortical projection neurons in the mouse cortices of the same ages. Methods: E13.5, E15.5 and P0 control and mutant cortices were carefully dissected under a clean environment. Then total RNA was isolated using an RNeasy Mini Kit (QIAGEN) according to the manufacturer’s protocol, quantified using NanoDrop ND-2000, and checked for RNA integrity using Agilent 2100 bioanalyzer. RNA-seq libraries were prepared according to the Illumina TruSeq protocol. Results: An average of 15 million reads per sample were obtained.
2021-08-31 | GSE182990 | GEO
Project description:Purpose: To assess changes in gene expression profiles from the P0 littermate Sp9Flox/Flox control striatum (including SVZ) and conditional mutant striatum of Drd2-Cre; Sp9Flox/Flox mice. Methods: total RNA was isolated and sequenced from the striatum of the P0 littermate Sp9Flox/Flox control or conditional mutant striatum of Drd2-Cre; Sp9Flox/Flox mice in triplicate using an Illumina high-seq 2500. Raw data was analyzed using TopHat. Genes were considered changed which demonstrated fold-change>=2, and p value <=0.05. Changed genes were then filtered to reveal Sp9 downstream targets which were altered in vivo due to the loss of Sp9 expression. Results: 179 genes were significantly increased and 147 genes were significantly decreased in expression level due to the loss of Sp9 expression. total RNA was isolated and sequenced from the striatum of the P0 littermate Sp9Flox/Flox control or conditional mutant striatum of Drd2-Cre; Sp9Flox/Flox mice in triplicate using an Illumina high-seq 2500. Raw data was analyzed using TopHat. Genes were considered changed which demonstrated fold-change>=2, and p value <=0.05. Changed genes were then filtered to reveal Sp9 downstream targets which were altered in vivo due to the loss of Sp9 expression.
2016-06-16 | E-GEOD-83373 | biostudies-arrayexpress
Project description:Purpose: To assess changes in gene expression profiles from the P0 littermate Sp9Flox/Flox control striatum (including SVZ) and conditional mutant striatum of Drd2-Cre; Sp9Flox/Flox mice. Methods: total RNA was isolated and sequenced from the striatum of the P0 littermate Sp9Flox/Flox control or conditional mutant striatum of Drd2-Cre; Sp9Flox/Flox mice in triplicate using an Illumina high-seq 2500. Raw data was analyzed using TopHat. Genes were considered changed which demonstrated fold-change>=2, and p value <=0.05. Changed genes were then filtered to reveal Sp9 downstream targets which were altered in vivo due to the loss of Sp9 expression. Results: 179 genes were significantly increased and 147 genes were significantly decreased in expression level due to the loss of Sp9 expression.
2016-06-16 | GSE83373 | GEO
Project description:Expression data from wild-type and Dazap1 mutant mouse testes
| PRJNA182339 | ENA
Project description:Dysregulation of the striatum is linked to multiple diseases including Huntington’s (HD), Parkinson’s, X-linked dystonia-parkinsonism (XDP), addiction, autism, and schizophrenia. Striatal medium spiny neurons (MSNs) make up 90% of the neuronal cell type in the striatum and are critical to motor control. The transcription factor Bcl11b (also known as CTIP2) is known to regulate of MSN differentiation, striatal striosome (patch) development and the architecture of the striatum during development. However, the function of Bcl11b adult striatal neurons in vivo has not been investigated. Therefore, we conditionally knocked out Bcl11b specifically in MSNs using D9-cre under the control of a regulatory elements of the mouse Ppp1r1b gene encoding DARPP-32 resulting in knockout around 5-6 weeks of age. Transcriptomic and behavioral analysis were performed on these mice.
2022-11-02 | GSE185476 | GEO
Project description:B-cell leukemia/lymphoma 11B (Bcl11b) is a transcription factor showing predominant expression in the striatum. To date, there are no known gene targets of Bcl11b in the nervous system. Here, we define targets for Bcl11b in striatal cells by performing genome-wide expression profiling. Transcriptome-wide analysis revealed that 694 genes were significantly altered in striatal cells over-expressing Bcl11b, including genes showing striatal-enriched expression similar to Bcl11b. Functional analysis on the gene target list identified significant association of Bcl11b to brain-derived neurotrophic factor/neurotrophin signaling. These data implicate Bcl11b as a novel regulator of the BDNF signaling pathway, which is disrupted in many neurological disorders. n=4 wt STHdh striatal cells and n=4 Bcl11b-transfected STHdh striatal cells
2011-08-01 | E-GEOD-31096 | biostudies-arrayexpress
Project description:<p>Although multi-agent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die due to chemo-refractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape and pattern of clonal evolution at relapse in pediatric ALL cases. These analyses showed that ALL relapses originate from a common ancestral precursor clone of the diagnosis and relapsed populations and frequently harbor mutations implicated in chemotherapy resistance. RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Notably, while some cases showed emergence of RAS mutant clones at relapse, in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations. Mechanistically, functional dissection of mouse and human wild type Kras and mutant Kras (Kras G12D) isogenic leukemia cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras- expressing lymphoblasts. These results identify chemotherapy driven selection as a central mechanism of leukemia clonal evolution and pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL. </p>
| phs001072 | dbGaP