Gene regulatory networks controlling differentiation, survival, and diversification of hypothalamic Lhx6-expressing GABAergic neurons

Kim, Dong Won; Li, Kai; Wang, Zoe Qianyi; Zhang, Yi Stephanie; Bathini, Abhijith; Brown, Matthew; Lin, Sonia Hao; Washington, Parris Whitney; Sun, Cuiyun; Lindtner, Susan; Lee, Bora; Wang, Hong; Shimogori, Tomomi; Rubenstein, John L.R.; Blackshaw, Seth

doi:10.1101/2020.05.21.106963

Cited by 12 publications

(12 citation statements)

References 77 publications

(136 reference statements)

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“…Brain cell dissociation was performed as described previously (Bell et al 2021;Kim et al 2021) using one female mouse per genotype. Mouse brain matrix (0.5 mm) was used to slice brains into coronal sections, and relative brain regions (cerebral cortex, striatum, midbrain) were dissected into Hibernate-A media with a 2% B-27 and GlutaMAX supplement (0.5 mM final).…”

Section: Cell Dissociation and Scrna-seqmentioning

confidence: 99%

Ptbp1 deletion does not induce glia-to-neuron conversion in adult mouse retina and brain

Hoang

Kim

Appel

et al. 2021

Preprint

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Somatic reprogramming of glia into neurons is a potentially promising approach for the replacement of neurons lost to injury or neurodegenerative disorders. Knockdown of the polypyrimidine tract-binding protein Ptbp1 has been recently reported to induce efficient conversion of retinal Mϋller glia and brain astrocytes into functional neurons. However, genetic analysis of Ptbp1 function in adult glia has not been conducted. Here, we use a combination of genetic lineage tracing, scRNA-Seq, and electrophysiological analysis to show that specific deletion of Ptbp1 in adult retinal Mϋller glia and brain astrocytes does not lead to any detectable level of glia-to-neuron conversion. Few changes in gene expression are observed in glia following Ptbp1 deletion, and glial identity is maintained. These findings highlight the importance of using genetic manipulation and lineage tracing methods in studying cell type conversion.

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Section: Cell Dissociation and Scrna-seqmentioning

confidence: 99%

Ptbp1 deletion does not induce glia-to-neuron conversion in adult mouse retina and brain

Hoang

Kim

Appel

et al. 2021

Preprint

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“…Mouse cortices were collected and dissociated using a previously published protocol 65,66 . Basically, cerebral cortices and hippocampi were dissected into Hibernate-A media with a 2% B-27 and GlutaMAX supplement (0.5 mM final).…”

Section: Methodsmentioning

confidence: 99%

Amyloid-beta and tau pathologies are both necessary to induce novel stage-specific microglia subtypes during Alzheimer’s disease progression

Kim

Wei

et al. 2021

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It is unknown whether specific microglia are selectively induced by amyloid-β(Aβ), tau pathologies, or both in combination. To address this, we use single-cell RNA-sequencing to profile mice bearing both Aβ and tau pathologies during Alzheimer's disease (AD). We identify novel microglia subtypes induced in a disease stage-specific manner. We show that during early-stage disease, interferon signaling induces a subtype of microglia termed EADAM. During late-stage disease, a second microglia subtype termed LADAM is detected. While EADAM and LADAM-like microglia are observed in other neurodegenerative models, the magnitude and composition of subtype markers are distinct from microglia observed with AD-like pathology. The pattern of EADAM- and LADAM-associated gene expression is observed in microglia from human AD, during the early and late stages of disease, respectively. Furthermore, we observe that several siglec genes are selectively expressed in either EADAM or LADAM. Siglecg is expressed in white-matter-associated LADAM, and expression of the human orthologue of Siglecg is progressively elevated in AD-stage-dependent manner but not shown in non-AD tauopathy. Our findings imply that both Aβ and tau pathologies are required for disease stage-specific induction of EADAM and LADAM.

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“…SCENIC 29 was used to calculate regulons controlling gene expressions across adipocytes differentiation stages as previously described. 30,31 Enriched genes from control and TAO bulk RNA-Seq datasets were superimposed on in vitro dataset using Seurat AddModuleScore function.…”

Section: Methodsmentioning

confidence: 99%

Transcriptomic profiling of human orbital fat and differentiating orbital fibroblasts

Taneja

Hoang

et al. 2021

Preprint

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Purpose: Orbital fat hyperplasia has a central role in the manifestations of thyroid-associated orbitopathy (TAO). To better understand the pathways involved in adipogenesis in TAO, we have used transcriptomic methods to analyze gene expression in control and TAO patients, as well as in differentiating orbital fibroblasts (OFs). Methods: We performed bulk RNA sequencing (RNA-Seq) on intraconal orbital fat to compare gene expression in control and TAO patients. We treated cultured OFs derived from TAO patients with media containing dexamethasone, insulin, rosiglitazone, and isobutylmethylxanthine (IBMX) to induce adipogenesis. We used single nuclear RNA-Seq (snRNA-Seq) profiling of treated OFs to compare gene expression over time in order to identify pathways that are involved in orbital adipogenesis in vitro and compared the dynamic patterns of gene expression identify differences in gene expression in control and TAO orbital fat. Results: Orbital fat from TAO and control patients segregate with principal component analysis (PCA). Numerous signaling pathways are enriched in orbital fat isolated from TAO patients. SnRNA-Seq of orbital fibroblasts undergoing adipogenesis reveals differential expression of adipocyte-specific genes over the developmental time course. Furthermore, genes that are enriched in TAO orbital fat are also upregulated in orbital adipocytes that differentiate in vitro, while genes that are enriched in control orbital fat are enriched in orbital fibroblasts prior to differentiation. Conclusions: Differentiating orbital fibroblasts serve as a model to study orbital fat hyperplasia seen in TAO. We demonstrate that the insulin-like growth factor-1 receptor (IGF-1R) and Wnt signaling pathways are differentially expressed early in orbital adipogenesis.

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Gene regulatory networks controlling differentiation, survival, and diversification of hypothalamic Lhx6-expressing GABAergic neurons

Cited by 12 publications

References 77 publications

Ptbp1 deletion does not induce glia-to-neuron conversion in adult mouse retina and brain

Ptbp1 deletion does not induce glia-to-neuron conversion in adult mouse retina and brain

Amyloid-beta and tau pathologies are both necessary to induce novel stage-specific microglia subtypes during Alzheimer’s disease progression

Transcriptomic profiling of human orbital fat and differentiating orbital fibroblasts

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