Transcriptomic Profiling of Developing Melanocortin Neurons Reveals a Role for Prdm12 in Energy Balance

AbstractThe hypothalamus is a critical regulator of many physiological processes essential for life. In the adult brain, each anatomically-defined hypothalamic nucleus consists of functionally heterogeneous neuronal subpopulations that dictate distinct survival behaviors. Nevertheless, how rich neuronal identities are established in the developing hypothalamus remains poorly understood.Despite their opposing actions on food intake, POMC and NPY/AgRP neurons in the arcuate nucleus of the hypothalamus (ARH) are derived from the same progenitors that give rise to ARH neurons. However, the mechanism whereby common neuronal precursors subsequently adopt either the anorexigenic (POMC) or the orexigenic (NPY/AgRP) identity remains elusive.We hypothesize that POMC and NPY/AgRP cell fates are specified and maintained by distinct intrinsic factors. In search of them, we profiled the transcriptomes of developing POMC and NPY/AgRP neurons with whole-genome RNA sequencing (RNA-seq). Moreover, cell-type-specific transcriptomic analyses revealed transcription regulators that are selectively enriched in either population, but whose developmental functions are unknown in these neurons.Among them, we found the expression of the PR domain-containing factor 12 (Prdm12) was enriched in POMC neurons but was absent in NPY/AgRP neurons. Selective ablation of Prdm12 in postmitotic POMC neurons led to early-onset obesity, accelerated linear growth, as well as impaired glucose tolerance, which recapitulates symptoms of POMC/MC4R deficiency in humans. These findings, therefore, establish a previously-unrecognized role for Prdm12 in energy balance. Furthermore, the combination of cell-type-specific genomic and genetic analyses provides a means to dissect cellular and functional diversity in the developing hypothalamus as well as the developmental origins of diverse survival behaviors.

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The Cell Type–Specific Functions of miR-21 in Cardiovascular Diseases

Frontiers in Genetics ◽

10.3389/fgene.2020.563166 ◽

2020 ◽

Vol 11 ◽

Author(s):

Beibei Dai ◽

Feng Wang ◽

Xiang Nie ◽

Hengzhi Du ◽

Yanru Zhao ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Vascular System ◽

Cardiac Fibroblasts ◽

Pressure Overload ◽

Cell Type ◽

Physiological Processes ◽

A Cell ◽

Cell Type Specific ◽

Underlying Mechanisms ◽

Endothelial Nitric Oxide

Cardiovascular diseases are one of the prime reasons for disability and death worldwide. Diseases and conditions, such as hypoxia, pressure overload, infection, and hyperglycemia, might initiate cardiac remodeling and dysfunction by inducing hypertrophy or apoptosis in cardiomyocytes and by promoting proliferation in cardiac fibroblasts. In the vascular system, injuries decrease the endothelial nitric oxide levels and affect the phenotype of vascular smooth muscle cells. Understanding the underlying mechanisms will be helpful for the development of a precise therapeutic approach. Various microRNAs are involved in mediating multiple pathological and physiological processes in the heart. A cardiac enriched microRNA, miR-21, which is essential for cardiac homeostasis, has been demonstrated to act as a cell–cell messenger with diverse functions. This review describes the cell type–specific functions of miR-21 in different cardiovascular diseases and its prospects in clinical therapy.

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Mechanisms Underlying Hox-Mediated Transcriptional Outcomes

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.787339 ◽

2021 ◽

Vol 9 ◽

Author(s):

Brittany Cain ◽

Brian Gebelein

Keyword(s):

Transcription Factors ◽

Differentially Express ◽

Target Genes ◽

Cell Type ◽

Cell Fates ◽

Specific Manner ◽

A Cell ◽

Cell Type Specific ◽

Anterior Posterior ◽

Anterior Posterior Axis

Metazoans differentially express multiple Hox transcription factors to specify diverse cell fates along the developing anterior-posterior axis. Two challenges arise when trying to understand how the Hox transcription factors regulate the required target genes for morphogenesis: First, how does each Hox factor differ from one another to accurately activate and repress target genes required for the formation of distinct segment and regional identities? Second, how can a Hox factor that is broadly expressed in many tissues within a segment impact the development of specific organs by regulating target genes in a cell type-specific manner? In this review, we highlight how recent genomic, interactome, and cis-regulatory studies are providing new insights into answering these two questions. Collectively, these studies suggest that Hox factors may differentially modify the chromatin of gene targets as well as utilize numerous interactions with additional co-activators, co-repressors, and sequence-specific transcription factors to achieve accurate segment and cell type-specific transcriptional outcomes.

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Cell-type specific patterned stimulus-independent neuronal activity in the Drosophila visual system during synapse formation

10.1101/376871 ◽

2018 ◽

Author(s):

Orkun Akin ◽

Bryce T. Bajar ◽

Mehmet F. Keles ◽

Mark A. Frye ◽

S. Lawrence Zipursky

Keyword(s):

Visual System ◽

Synapse Formation ◽

Neural Circuit ◽

Specific Activity ◽

System Development ◽

Nervous System Development ◽

Adult Brain ◽

Cell Type ◽

Cell Type Specific

SummaryStereotyped synaptic connections define the neural circuits of the brain. In vertebrates, stimulus-independent activity contributes to neural circuit formation. It is unknown whether this type of activity is a general feature of nervous system development. Here, we report patterned, stimulus-independent neural activity in the Drosophila visual system during synaptogenesis. Using in vivo calcium, voltage, and glutamate imaging, we found that all neurons participate in this spontaneous activity, which is characterized by brain-wide periodic active and silent phases. Glia are active in a complementary pattern. Each of the 15 examined of the over 100 specific neuron types in the fly visual system exhibited a unique activity signature. The activity of neurons that are synaptic partners in the adult was highly correlated during development. We propose that this cell type-specific activity coordinates the development of the functional circuitry of the adult brain.

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COMP-16. COMPREHENSIVE TRANSCRIPTOMIC ANALYSIS OF SINGLE CELLS FROM RECURRENT AND PRIMARY GLIOBLASTOMA TO PREDICT CELL-TYPE SPECIFIC THERAPEUTICS

Neuro-Oncology ◽

10.1093/neuonc/noz175.259 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi64-vi64

Author(s):

Robert Suter ◽

Vasileios Stathias ◽

Anna Jermakowicz ◽

Alexa Semonche ◽

Michael Ivan ◽

...

Keyword(s):

Single Cell ◽

Rna Sequencing ◽

Tumor Heterogeneity ◽

Drug Response ◽

Adult Brain ◽

Cell Populations ◽

Cell Type ◽

Single Cell Rna Sequencing ◽

Cell Type Specific ◽

Recurrent Gbm

Abstract Glioblastoma (GBM) remains the most common adult brain tumor, with poor survival expectations, and no new therapeutic modalities approved in the last decade. Our laboratories have recently demonstrated that the integration of a transcriptional disease signature obtained from The Cancer Genome Atlas’ GBM dataset with transcriptional cell drug-response signatures in the LINCS L1000 dataset yields possible combinatorial therapeutics. Considering the extreme intra-tumor heterogeneity associated with the disease, we hypothesize that the utilization of single-cell RNA-sequencing (scRNA-seq) of patient tumors will further strengthen our predictive model by providing insight on the unique transcriptomes of the cellular niches present within these tumors, and into the transcriptional dynamics of these same cellular niches. By sequencing single-cell transcriptomes from recurrent GBM tumors resected from patients at the University of Miami, and integrating our datasets with previously published scRNA-seq data from primary GBM tumors, we are able to gain additional insight into the differences between these clinical distinctions. We have analyzed the differential expression of kinases both across and within distinct cell populations of primary and recurrent GBM tumors. This transcriptional map of kinase expression represents the heterogeneity of potential targets within individual tumors and between recurrent and primary GBM. Additionally, by generating disease signatures unique to each cellular population, and integrating these with transcriptional drug-response signatures from LINCS, we are able to predict compounds to target specific cell populations within GMB tumors. Additional computational techniques such as RNA velocity analysis and cell cycle scoring elucidate temporal insights to further prioritize these cell-type specific therapeutics, and reveal the intra-cellular dynamics present within these tumors. Collectively, our studies suggest that we have developed a novel omics pipeline based on the single cell RNA-sequencing of individual GBM cells that addresses intra-tumor heterogeneity, and may lead to novel therapeutic combinations for the treatment of this incurable disease.

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Cell-Type-Specific and Regulatable Transgenesis in the Adult Brain: Adenovirus-Encoded Combined Transcriptional Targeting and Inducible Transgene Expression

Molecular Therapy ◽

10.1006/mthe.2000.0215 ◽

2000 ◽

Vol 2 (6) ◽

pp. 579-587 ◽

Cited By ~ 60

Author(s):

Joseph R. Smith-Arica ◽

Adrian E. Morelli ◽

Adriana T. Larregina ◽

John Smith ◽

Pedro R. Lowenstein ◽

...

Keyword(s):

Transgene Expression ◽

Adult Brain ◽

Cell Type ◽

Transcriptional Targeting ◽

Cell Type Specific

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Knockdown of the Fat Mass and Obesity Gene Disrupts Cellular Energy Balance in a Cell-Type Specific Manner

PLoS ONE ◽

10.1371/journal.pone.0038444 ◽

2012 ◽

Vol 7 (6) ◽

pp. e38444 ◽

Cited By ~ 12

Author(s):

Ryan T. Pitman ◽

Jason T. Fong ◽

Penny Billman ◽

Neelu Puri

Keyword(s):

Energy Balance ◽

Fat Mass ◽

Cell Type ◽

Obesity Gene ◽

Cellular Energy ◽

Specific Manner ◽

A Cell ◽

Cell Type Specific

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Single-cell transcriptomics characterizes cell types in the subventricular zone and uncovers molecular defects underlying impaired adult neurogenesis

10.1101/365619 ◽

2018 ◽

Author(s):

Vera Zywitza ◽

Aristotelis Misios ◽

Lena Bunatyan ◽

Thomas E. Willnow ◽

Nikolaus Rajewsky

Keyword(s):

Single Cell ◽

Adult Neurogenesis ◽

Subventricular Zone ◽

Single Cells ◽

Cell Types ◽

Neural Cell ◽

Adult Brain ◽

List Type ◽

Cell Type ◽

Cell Type Specific

SUMMARYNeural stem cells (NSCs) contribute to plasticity and repair of the adult brain. Niches harboring NSCs are crucial for regulating stem cell self-renewal and differentiation. We used single-cell RNA profiling to generate an unbiased molecular atlas of all cell types in the largest neurogenic niche of the adult mouse brain, the subventricular zone (SVZ). We characterized > 20 neural and non-neural cell types and gained insights into the dynamics of neurogenesis by predicting future cell states based on computational analysis of RNA kinetics. Furthermore, we apply our single-cell approach to mice lacking LRP2, an endocytic receptor required for SVZ maintenance. The number of NSCs and proliferating progenitors was significantly reduced. Moreover, Wnt and BMP4 signaling was perturbed. We provide a valuable resource for adult neurogenesis, insights into SVZ neurogenesis regulation by LRP2, and a proof-of-principle demonstrating the power of single-cell RNA-seq in pinpointing neural cell type-specific functions in loss-of-function models.HIGHLIGHTSunbiased single-cell transcriptomics characterizes adult NSCs and their nichecell type-specific signatures and marker genes for 22 SVZ cell typesFree online tool to assess gene expression across 9,804 single cellscell type-specific dysfunctions underlying impaired adult neurogenesis

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Inflammatory Cytokines IL-1β and TNF-α Regulate p75NTR Expression in CNS Neurons and Astrocytes by Distinct Cell-Type-Specific Signalling Mechanisms

ASN NEURO ◽

10.1042/an20090009 ◽

2009 ◽

Vol 1 (2) ◽

pp. AN20090009 ◽

Cited By ~ 36

Author(s):

Soyoung Choi ◽

Wilma J Friedman

Keyword(s):

Inflammatory Cytokines ◽

Interleukin 1 ◽

Nuclear Factor Κb ◽

Adult Brain ◽

Mitogen Activated Protein Kinase ◽

Neurotrophin Receptor ◽

Cell Type ◽

Distinct Cell Type ◽

Tnf Α ◽

Cell Type Specific

The p75NTR (where NTR is neurotrophin receptor) can mediate many distinct cellular functions, including cell survival and apoptosis, axonal growth and cell proliferation, depending on the cellular context. This multifunctional receptor is widely expressed in the CNS (central nervous system) during development, but its expression is restricted in the adult brain. However, p75NTR is induced by a variety of pathophysiological insults, including seizures, lesions and degenerative disease. We have demonstrated previously that p75NTR is induced by seizures in neurons, where it induces apoptosis, and in astrocytes, where it may regulate proliferation. In the present study, we have investigated whether the inflammatory cytokines IL (interleukin)-1 β and TNF- α (tumour necrosis factor- α), that are commonly elevated in these pathological conditions, mediate the regulation of p75NTR in neurons and astrocytes. We have further analysed the signal transduction pathways by which these cytokines induce p75NTR expression in the different cell types, specifically investigating the roles of the NF- κB (nuclear factor κB) and p38 MAPK (mitogen-activated protein kinase) pathways. We have demonstrated that both cytokines regulate p75NTR expression; however, the mechanisms governing this regulation are cytokine- and cell-type specific. The distinct mechanisms of cytokine-mediated p75NTR regulation that we demonstrate in the present study may facilitate therapeutic intervention in regulation of this receptor in a cell-selective manner.

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Plasticity of Neural Connections Underlying Oxytocin-mediated Parental Behaviors of Male Mice

10.1101/2021.10.20.465207 ◽

2021 ◽

Author(s):

Kengo Inada ◽

Mitsue Hagihara ◽

Kazuko Tsujimoto ◽

Takaya Abe ◽

Ayumu Konno ◽

...

Keyword(s):

Behavioral Plasticity ◽

Life Stage ◽

Adult Brain ◽

Male Mice ◽

Cell Type ◽

Long Distance ◽

Neural Connections ◽

Parental Caregiving ◽

Cell Type Specific ◽

The Brain

The adult brain can flexibly adapt behaviors to specific life-stage demands. For example, while sexually naïve male mice are aggressive to the conspecific young, they start to provide caregiving to infants around the time when their own young are expected. How such behavioral plasticity is implemented at the level of neural connections remains poorly understood. Using viral-genetic approaches, here we establish hypothalamic oxytocin neurons as key regulators of parental caregiving behaviors of male mice. We then used rabies virus-mediated unbiased screen to identify excitatory neural connections originating from the lateral hypothalamus to the oxytocin neurons to be drastically strengthened when male mice become fathers. These connections are functionally relevant, as their activation suppresses pup-directed aggression in virgin males. These results demonstrate the life-stage associated, long-distance, and cell-type-specific plasticity of neural connections in the hypothalamus, the brain region classically assumed to be hard-wired.

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