Project description:Use of single-cell transcriptomics to measure how well medium spiny projection neurons, derived from human ESC, recapitulate human striatal development in vivo. This in vitro single-cell dataset was derived after exposing hESC lines (H9) to a novel striatal differentiation protocol and performing single-cell RNA-seq after 15 days and 25 days of differentiation.
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.
Project description:We knocked out ERK1 and ERK2 in the striatopallidal population of striatal medium spiny neurons and analyzed differences in gene expression at P17, a time of increased synapse formation. We used whole gene microarray to assess transcriptional changes that occur in the mouse striatum at P17 in response to ERK1/2 deletion in striatopallidal medium spiny neurons.
Project description:To understand the developing striatum, key genes during development were identified using microarray analsyis tha could be considered as marker of medium spiny neurons. The ages studied is at peak striatal neurogenesis.
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
Project description:Constitutive knockout of the obsessive-compulsive disorder-associated protein, SAPAP3, results in repetitive motor dysfunction, such as excessive grooming, caused by increased mGluR5 activity in striatal medium spiny neurons (MSNs). However, signaling mechanisms that mediate mGluR5-dependent grooming dysfunction are not fully understood. Here, we investigate the function of the striatal signaling hub protein, spinophilin, in regulating mGluR5 phosphorylation and protein interactions, which may predict spinophilin’s role in regulating mGluR5-dependent grooming dysfunction.
Project description:To understand the developing striatum, key genes during development were identified using microarray analsyis tha could be considered as marker of medium spiny neurons. The ages studied is at peak striatal neurogenesis. 3 different gestational ages of CD1 mice were used with triplicate repeats
Project description:Genome binding/occupancy profiling was carried out by high throughput sequencing in human developmental cortical interneurons and developmental glutamatergic neurons derived from healthy control vs schizophrenia iPSCs
Project description:To gain insight into how mutant Huntingtin (mHTT) CAG repeat length may modify Huntington’s disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat length. We find repeat length dependent transcriptional signatures are prominent in the striatum, less so in cortex, and minimal in the liver. Co-expression network analyses reveal 13 striatal and 5 cortical modules that are highly correlated with CAG length and age, and that are preserved in HD models and some in the patients. Top striatal modules implicate mHTT CAG length and age in graded impairment of striatal medium spiny neuron identity gene expression and in dysregulation of cAMP signaling, cell death, and protocadherin genes. Importantly, we used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at both RNA and protein levels and validated 21 striatal module genes as modifiers of mHtt toxicities in vivo.
