IgSF11 homophilic adhesion proteins promote layer-specific synaptic assembly of the cortical interneuron subtype

The most prominent structural hallmark of the mammalian neocortical circuitry is the layer-based organization of specific cell types and synaptic inputs. Accordingly, cortical inhibitory interneurons (INs), which shape local network activity, exhibit subtype-specific laminar specificity of synaptic outputs. However, the underlying molecular mechanisms remain unknown. Here, we demonstrate that Immunoglobulin Superfamily member 11 (IgSF11) homophilic adhesion proteins are preferentially expressed in one of the most distinctive IN subtypes, namely, chandelier cells (ChCs) that specifically innervate axon initial segments of pyramidal neurons (PNs), and their synaptic laminar target. Loss-of-function experiments in either ChCs or postsynaptic cells revealed that IgSF11 is required for ChC synaptic development in the target layer. While overexpression of IgSF11 in ChCs enlarges ChC presynaptic boutons, expressing IgSF11 in nontarget layers induces ectopic ChC synapses. These findings provide evidence that synapse-promoting adhesion proteins, highly localized to synaptic partners, determine the layer-specific synaptic connectivity of the cortical IN subtype.

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par-4, a gene required for cytoplasmic localization and determination of specific cell types in Caenorhabditis elegans embryogenesis.

Genetics ◽

10.1093/genetics/130.4.771 ◽

1992 ◽

Vol 130 (4) ◽

pp. 771-790 ◽

Cited By ~ 5

Author(s):

D G Morton ◽

J M Roos ◽

K J Kemphues

Keyword(s):

Caenorhabditis Elegans ◽

Cell Types ◽

Intestinal Cells ◽

Specific Cell ◽

Cytoplasmic Localization ◽

Loss Of Function ◽

Embryo Viability ◽

Cell Stage ◽

Maternal Genome

Abstract Specification of some cell fates in the early Caenorhabditis elegans embryo is mediated by cytoplasmic localization under control of the maternal genome. Using nine newly isolated mutations, and two existing mutations, we have analyzed the role of the maternally expressed gene par-4 in cytoplasmic localization. We recovered seven new par-4 alleles in screens for maternal effect lethal mutations that result in failure to differentiate intestinal cells. Two additional par-4 mutations were identified in noncomplementation screens using strains with a high frequency of transposon mobility. All 11 mutations cause defects early in development of embryos produced by homozygous mutant mothers. Analysis with a deficiency in the region indicates that it33 is a strong loss-of-function mutation. par-4(it33) terminal stage embryos contain many cells, but show no morphogenesis, and are lacking intestinal cells. Temperature shifts with the it57ts allele suggest that the critical period for both intestinal differentiation and embryo viability begins during oogenesis, about 1.5 hr before fertilization, and ends before the four-cell stage. We propose that the primary function of the par-4 gene is to act as part of a maternally encoded system for cytoplasmic localization in the first cell cycle, with par-4 playing a particularly important role in the determination of intestine. Analysis of a par-4; par-2 double mutant suggests that par-4 and par-2 gene products interact in this system.

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Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens

Molecular Psychiatry ◽

10.1038/s41380-021-01217-8 ◽

2021 ◽

Author(s):

Hee-Dae Kim ◽

Jing Wei ◽

Tanessa Call ◽

Nicole Teru Quintus ◽

Alexander J. Summers ◽

...

Keyword(s):

Nucleus Accumbens ◽

Molecular Mechanisms ◽

Cell Types ◽

Current Treatment ◽

Specific Cell ◽

Excitatory Synapses ◽

Cell Type ◽

Cell Type Specific ◽

Specific Regulation ◽

Circuit Function

AbstractDepression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

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Assessment of phagocytic activity in live macrophages-tumor cells co-cultures by Confocal and Nomarski Microscopy

Biology Methods and Protocols ◽

10.1093/biomethods/bpx002 ◽

2017 ◽

Vol 2 (1) ◽

Cited By ~ 5

Author(s):

Dalia Martinez-Marin ◽

Courtney Jarvis ◽

Thomas Nelius ◽

Stéphanie Filleur

Keyword(s):

Tumor Microenvironment ◽

Tumor Cells ◽

Phagocytic Activity ◽

Molecular Mechanisms ◽

Cell Types ◽

Functional Assay ◽

Loss Of Function ◽

Multiple Cancer

Abstract Macrophages have been recognized as the main inflammatory component of the tumor microenvironment. Although often considered as beneficial for tumor growth and disease progression, tumor-associated macrophages have also been shown to be detrimental to the tumor depending on the tumor microenvironment. Therefore, understanding the molecular interactions between macrophages and tumor cells in relation to macrophages functional activities such as phagocytosis is critical for a better comprehension of their tumor-modulating action. Still, the characterization of these molecular mechanisms in vivo remains complicated due to the extraordinary complexity of the tumor microenvironment and the broad range of tumor-associated macrophage functions. Thus, there is an increasing demand for in vitro methodologies to study the role of cell–cell interactions in the tumor microenvironment. In the present study, we have developed live co-cultures of macrophages and human prostate tumor cells to assess the phagocytic activity of macrophages using a combination of Confocal and Nomarski Microscopy. Using this model, we have emphasized that this is a sensitive, measurable, and highly reproducible functional assay. We have also highlighted that this assay can be applied to multiple cancer cell types and used as a selection tool for a variety of different types of phagocytosis agonists. Finally, combining with other studies such as gain/loss of function or signaling studies remains possible. A better understanding of the interactions between tumor cells and macrophages may lead to the identification of new therapeutic targets against cancer.

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Transforming Growth Factor β-Mediated Transcriptional Repression of c-myc Is Dependent on Direct Binding of Smad3 to a Novel Repressive Smad Binding Element

Molecular and Cellular Biology ◽

10.1128/mcb.24.6.2546-2559.2004 ◽

2004 ◽

Vol 24 (6) ◽

pp. 2546-2559 ◽

Cited By ~ 159

Author(s):

Joshua P. Frederick ◽

Nicole T. Liberati ◽

David S. Waddell ◽

Yigong Shi ◽

Xiao-Fan Wang

Keyword(s):

Growth Factor ◽

Transcriptional Repression ◽

Molecular Mechanisms ◽

Target Genes ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Cell Types ◽

Specific Cell ◽

Smad Proteins ◽

Smad Binding Element

ABSTRACT Smad proteins are the most well-characterized intracellular effectors of the transforming growth factor β (TGF-β) signal. The ability of the Smads to act as transcriptional activators via TGF-β-induced recruitment to Smad binding elements (SBE) within the promoters of TGF-β target genes has been firmly established. However, the elucidation of the molecular mechanisms involved in TGF-β-mediated transcriptional repression are only recently being uncovered. The proto-oncogene c-myc is repressed by TGF-β, and this repression is required for the manifestation of the TGF-β cytostatic program in specific cell types. We have shown that Smad3 is required for both TGF-β-induced repression of c-myc and subsequent growth arrest in keratinocytes. The transcriptional repression of c-myc is dependent on direct Smad3 binding to a novel Smad binding site, termed a repressive Smad binding element (RSBE), within the TGF-β inhibitory element (TIE) of the c-myc promoter. The c-myc TIE is a composite element, comprised of an overlapping RSBE and a consensus E2F site, that is capable of binding at least Smad3, Smad4, E2F-4, and p107. The RSBE is distinct from the previously defined SBE and may partially dictate, in conjunction with the promoter context of the overlapping E2F site, whether the Smad3-containing complex actively represses, as opposed to transactivates, the c-myc promoter.

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Misregulation of SDF1-CXCR4 Signaling Impairs Early Cardiac Neural Crest Cell Migration Leading to Conotruncal Defects

Circulation Research ◽

10.1161/circresaha.113.301333 ◽

2013 ◽

Vol 113 (5) ◽

pp. 505-516 ◽

Cited By ~ 52

Author(s):

Sophie Escot ◽

Cédrine Blavet ◽

Sonja Härtle ◽

Jean-Loup Duband ◽

Claire Fournier-Thibault

Keyword(s):

Neural Crest ◽

Molecular Mechanisms ◽

Heart Diseases ◽

Smooth Muscles ◽

Neural Crest Cell ◽

Cell Types ◽

Ventricular Septum ◽

Embryonic Cells ◽

Loss Of Function ◽

Cardiac Neural Crest

Rationale: Cardiac neural crest cells (NCs) contribute to heart morphogenesis by giving rise to a variety of cell types from mesenchyme of the outflow tract, ventricular septum, and semilunar valves to neurons of the cardiac ganglia and smooth muscles of the great arteries. Failure in cardiac NC development results in outflow and ventricular septation defects commonly observed in congenital heart diseases. Cardiac NCs derive from the vagal neural tube, which also gives rise to enteric NCs that colonize the gut; however, so far, molecular mechanisms segregating these 2 populations and driving cardiac NC migration toward the heart have remained elusive. Objective: Stromal-derived factor-1 (SDF1) is a chemokine that mediates oriented migration of multiple embryonic cells and mice deficient for Sdf1 or its receptors, Cxcr4 and Cxcr7 , exhibit ventricular septum defects, raising the possibility that SDF1 might selectively drive cardiac NC migration toward the heart via a chemotactic mechanism. Methods and Results : We show in the chick embryo that Sdf1 expression is tightly coordinated with the progression of cardiac NCs expressing Cxcr4 . Cxcr4 loss-of-function causes delayed migration and enhanced death of cardiac NCs, whereas Sdf1 misexpression results in their diversion from their normal pathway, indicating that SDF1 acts as a chemoattractant for cardiac NCs. These alterations of SDF1 signaling result in severe cardiovascular defects. Conclusions: These data identify Sdf1 and its receptor Cxcr4 as candidate genes responsible for cardiac congenital pathologies in human.

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Untangling stability and gain modulation in cortical circuits with multiple interneuron classes

10.1101/2020.06.15.148114 ◽

2020 ◽

Cited By ~ 1

Author(s):

Hannah Bos ◽

Anne-Marie Oswald ◽

Brent Doiron

Keyword(s):

Pyramidal Neurons ◽

Mean Field ◽

Gain Control ◽

Cell Types ◽

High Gain ◽

Cortical Inhibition ◽

Network Activity ◽

Inhibitory Neurons ◽

Neuron Models ◽

Cortical Circuit

AbstractSynaptic inhibition is the mechanistic backbone of a suite of cortical functions, not the least of which is maintaining overall network stability as well as modulating neuronal gain. Past cortical models have assumed simplified recurrent networks in which all inhibitory neurons are lumped into a single effective pool. In such models the mechanics of inhibitory stabilization and gain control are tightly linked in opposition to one another – meaning high gain coincides with low stability and vice versa. This tethering of stability and response gain restricts the possible operative regimes of the network. However, it is now well known that cortical inhibition is very diverse, with molecularly distinguished cell classes having distinct positions within the cortical circuit. In this study, we analyze populations of spiking neuron models and associated mean-field theories capturing circuits with pyramidal neurons as well as parvalbumin (PV) and somatostatin (SOM) expressing interneurons. Our study outlines arguments for a division of labor within the full cortical circuit where PV interneurons are ideally positioned to stabilize network activity, whereas SOM interneurons serve to modulate pyramidal cell gain. This segregation of inhibitory function supports stable cortical dynamics over a large range of modulation states. Our study offers a blueprint for how to relate the circuit structure of cortical networks with diverse cell types to the underlying population dynamics and stimulus response.

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Single-Cell Genomics: Catalyst for Cell Fate Engineering

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.748942 ◽

2021 ◽

Vol 9 ◽

Author(s):

Boxun Li ◽

Gary C. Hon

Keyword(s):

Single Cell ◽

Cell Fate ◽

Molecular Mechanisms ◽

Cell Types ◽

Cellular Heterogeneity ◽

State Transitions ◽

Small Scale ◽

Specific Cell ◽

Direct Reprogramming ◽

Cell State

As we near a complete catalog of mammalian cell types, the capability to engineer specific cell types on demand would transform biomedical research and regenerative medicine. However, the current pace of discovering new cell types far outstrips our ability to engineer them. One attractive strategy for cellular engineering is direct reprogramming, where induction of specific transcription factor (TF) cocktails orchestrates cell state transitions. Here, we review the foundational studies of TF-mediated reprogramming in the context of a general framework for cell fate engineering, which consists of: discovering new reprogramming cocktails, assessing engineered cells, and revealing molecular mechanisms. Traditional bulk reprogramming methods established a strong foundation for TF-mediated reprogramming, but were limited by their small scale and difficulty resolving cellular heterogeneity. Recently, single-cell technologies have overcome these challenges to rapidly accelerate progress in cell fate engineering. In the next decade, we anticipate that these tools will enable unprecedented control of cell state.

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Pituitary ontogeny of the Snell dwarf mouse reveals Pit-1-independent and Pit-1-dependent origins of the thyrotrope

Development ◽

10.1242/dev.120.3.515 ◽

1994 ◽

Vol 120 (3) ◽

pp. 515-522 ◽

Cited By ~ 12

Author(s):

S.C. Lin ◽

S. Li ◽

D.W. Drolet ◽

M.G. Rosenfeld

Keyword(s):

Molecular Mechanisms ◽

Cell Types ◽

Cell Phenotype ◽

Specific Cell ◽

Mutant Form ◽

Wild Type ◽

Pou Domain ◽

Distinct Cell ◽

Snell Dwarf ◽

Dwarf Mice

The anterior pituitary provides a model to study the molecular mechanisms responsible for emergence of distinct cell types within an organ. Dwarf mice (Snell) that express a mutant form of the tissue-specific POU-domain transcription factor Pit-1 fail to generate three cell types, including the thyrotrope (S. Li, E. B. Crenshaw, E. J. Rawson, D. S. Simmons, L. Swanson and M. G. Rosenfeld (1990), Nature 347, 528–533). Analyses of wild-type and Pit-1-defective mice, presented here, have revealed that thyrotropes unexpectedly arise from two independent cell populations. The first population is Pit-1-independent and appears on e12 in the rostral tip of the developing gland, but phenotypically disappears by the day of birth. The second is Pit-1-dependent and arises subsequently in the caudomedial portion of the developing gland (e15.5), following the initial expression of Pit-1 in this region. The failure of caudomedial thyrotrope cells to appear in the Snell dwarf, and the observation that Pit-1 can bind to and transactivate the TSH beta promoter, apparently enhanced by its phosphorylation, suggests that Pit-1 is directly required for the appearance of this distinct population that serves as the precursors of the mature thyrotrope cell type. These data suggest that different molecular mechanisms, based on the actions of distinct transcription factors, can serve to independently generate a specific cell phenotype during mammalian organogenesis.

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Controlling embryonic stem cell proliferation and pluripotency: the role of PI3K- and GSK-3-dependent signalling

Biochemical Society Transactions ◽

10.1042/bst0390674 ◽

2011 ◽

Vol 39 (2) ◽

pp. 674-678 ◽

Cited By ~ 24

Author(s):

Melanie J. Welham ◽

Emmajayne Kingham ◽

Yolanda Sanchez-Ripoll ◽

Benjamin Kumpfmueller ◽

Michael Storm ◽

...

Keyword(s):

Cell Fate ◽

Molecular Mechanisms ◽

Inner Cell Mass ◽

Glycogen Synthase ◽

Cell Mass ◽

Embryonic Stem ◽

Cell Types ◽

Specific Cell ◽

Human Escs ◽

Phosphoinositide 3 Kinase

ESCs (embryonic stem cells) are derived from the inner cell mass of pre-implantation embryos and are pluripotent, meaning they can differentiate into all of the cells that make up the adult organism. This property of pluripotency makes ESCs attractive as a model system for studying early development and for the generation of specific cell types for use in regenerative medicine and drug screening. In order to harness their potential, the molecular mechanisms regulating ESC pluripotency, proliferation and differentiation (i.e. cell fate) need to be understood so that pluripotency can be maintained during expansion, while differentiation to specific lineages can be induced accurately when required. The present review focuses on the potential roles that PI3K (phosphoinositide 3-kinase) and GSK-3 (glycogen synthase kinase 3)-dependent signalling play in the co-ordination and integration of mouse ESC pluripotency and proliferation and contrast this with our understanding of their functions in human ESCs.

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Leptin and Cancer: Updated Functional Roles in Carcinogenesis, Therapeutic Niches, and Developments

International Journal of Molecular Sciences ◽

10.3390/ijms22062870 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2870

Author(s):

Tsung-Chieh Lin ◽

Michael Hsiao

Keyword(s):

Cancer Progression ◽

Molecular Mechanisms ◽

Leptin Receptor ◽

Biological Effects ◽

Prognostic Significance ◽

Cell Types ◽

Receptor Expression ◽

Specific Cell ◽

Signaling Axis

Leptin is an obesity-associated adipokine that is known to regulate energy metabolism and reproduction and to control appetite via the leptin receptor. Recent work has identified specific cell types other than adipocytes that harbor leptin and leptin receptor expression, particularly in cancers and tumor microenvironments, and characterized the role of this signaling axis in cancer progression. Furthermore, the prognostic significance of leptin in various types of cancer and the ability to noninvasively detect leptin levels in serum samples have attracted attention for potential clinical applications. Emerging findings have demonstrated the direct and indirect biological effects of leptin in regulating cancer proliferation, metastasis, angiogenesis and chemoresistance, warranting the exploration of the underlying molecular mechanisms to develop a novel therapeutic strategy. In this review article, we summarize and integrate transcriptome and clinical data from cancer patients together with the recent findings related to the leptin signaling axis in the aforementioned malignant phenotypes. In addition, a comprehensive analysis of leptin and leptin receptor distribution in a pancancer panel and in individual cell types of specific organs at the single-cell level is presented, identifying those sites that are prone to leptin-mediated tumorigenesis. Our results shed light on the role of leptin in cancer and provide guidance and potential directions for further research for scientists in this field.

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