Structure of the heterophilic interaction between the nectin-like 4 and nectin-like 1 molecules

Nectin-like (Necl) molecules are Ca2+-independent Ig-like transmembrane cell adhesion molecules that participate in junctions between different cell types. The specific cell–cell adhesions mediated by Necl proteins are important in neural development and have been implicated in neurodegenerative diseases. Here, we present the crystal structure of the mouse Necl-4 full ectodomain and the structure of the heterophilic Necl ectodomain complex formed by the mNecl-4 and mNecl-1 ectodomains. We demonstrate that, while the ectodomain of mNecl-4 is monomeric, it forms a stable heterodimer with Ig1 of mNecl-1, with an affinity significantly higher than that observed for self-dimerization of the mNecl-1 ectodomain. We validated our structural characterizations by performing a surface plasmon resonance assay and an Fc fusion protein binding assay in mouse primary dorsal root ganglia neurites and Schwann cells and identified a selection of residues important for heterophilic interactions. Finally, we proposed a model of Necl binding specificity that involves an induced-fit conformational change at the dimerization interface.

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Extraneous E-Cadherin Engages the Deterministic Process of Somatic Reprogramming through Modulating STAT3 and Erk1/2 Activity

Cells ◽

10.3390/cells10020284 ◽

2021 ◽

Vol 10 (2) ◽

pp. 284

Author(s):

Yu-Hao Liu ◽

Chien-Chang Chen ◽

Yi-Jen Hsueh ◽

Li-Man Hung ◽

David Hui-Kang Ma ◽

...

Keyword(s):

Stochastic Process ◽

Molecular Mechanism ◽

Activity Ratio ◽

Cell Types ◽

Deterministic Process ◽

Modes Of Action ◽

Molecular Events ◽

Different Cell Types ◽

Selection Of ◽

E Cadherin

Although several modes of reprogramming have been reported in different cell types during iPSC induction, the molecular mechanism regarding the selection of different modes of action is still mostly unknown. The present study examined the molecular events that participate in the selection of such processes at the onset of somatic reprogramming. The activity of STAT3 versus that of Erk1/2 reversibly determines the reprogramming mode entered; a lower activity ratio favors the deterministic process and vice versa. Additionally, extraneous E-cadherin facilitates the early events of somatic reprogramming, potentially by stabilizing the LIF/gp130 and EGFR/ErbB2 complexes to promote entry into the deterministic process. Our current findings demonstrated that manipulating the pSTAT3/pErk1/2 activity ratio in the surrounding milieu can drive different modes of action toward either the deterministic or the stochastic process in the context of OSKM-mediated somatic reprogramming.

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Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma

eLife ◽

10.7554/elife.56782 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 5

Author(s):

Allison N Lau ◽

Zhaoqi Li ◽

Laura V Danai ◽

Anna M Westermark ◽

Alicia M Darnell ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Heterogeneous Systems ◽

Cell Types ◽

Ductal Adenocarcinoma ◽

Specific Cell ◽

Isolated Cells ◽

Pancreatic Cancer Cells ◽

Turn Over ◽

Different Cell Types

Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue.

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A transcription factor collective defines the HSN serotonergic neuron regulatory landscape

eLife ◽

10.7554/elife.32785 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 17

Author(s):

Carla Lloret-Fernández ◽

Miren Maicas ◽

Carlos Mora-Martínez ◽

Alejandro Artacho ◽

Ángela Jimeno-Martín ◽

...

Keyword(s):

De Novo ◽

Cell Types ◽

Specific Cell ◽

Serotonergic Neuron ◽

C Elegans ◽

Mouse Orthologs ◽

Deep Homology ◽

Regulatory Landscape ◽

Neuronal Type ◽

Selection Of

Cell differentiation is controlled by individual transcription factors (TFs) that together activate a selection of enhancers in specific cell types. How these combinations of TFs identify and activate their target sequences remains poorly understood. Here, we identify the cis-regulatory transcriptional code that controls the differentiation of serotonergic HSN neurons in Caenorhabditis elegans. Activation of the HSN transcriptome is directly orchestrated by a collective of six TFs. Binding site clusters for this TF collective form a regulatory signature that is sufficient for de novo identification of HSN neuron functional enhancers. Among C. elegans neurons, the HSN transcriptome most closely resembles that of mouse serotonergic neurons. Mouse orthologs of the HSN TF collective also regulate serotonergic differentiation and can functionally substitute for their worm counterparts which suggests deep homology. Our results identify rules governing the regulatory landscape of a critically important neuronal type in two species separated by over 700 million years.

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The role of SLAM family receptors in immune cell signalingThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB — Membrane Proteins in Health and Disease.

Biochemistry and Cell Biology ◽

10.1139/o06-191 ◽

2006 ◽

Vol 84 (6) ◽

pp. 832-843 ◽

Cited By ~ 14

Author(s):

Elena A. Ostrakhovitch ◽

Shawn S.-C. Li

Keyword(s):

Immune Cells ◽

Immune Cell ◽

Current Knowledge ◽

Critical Role ◽

Cell Types ◽

Health And Disease ◽

Slam Family ◽

Different Cell Types ◽

Selection Of

The signaling lymphocyte-activating molecule (SLAM) family immunoreceptors are expressed in a wide array of immune cells, including both T and B lymphocytes. By virtue of their ability to transduce tyrosine phosphorylation signals through the so-called ITSM (immunoreceptor tyrosine-based switch motif) sequences, they play an important part in regulating both innate and adaptive immune responses. The critical role of the SLAM immunoreceptors in mediating normal immune reactions was highlighted in recent findings that SAP, a SLAM-associated protein, modulates the activities of various immune cells through interactions with different members of the SLAM family expressed in these cells. Importantly, mutations or deletions of the sap gene in humans result in the X-linked lymphoproliferative syndrome. In this review, we summarize current knowledge and survey the latest developments in signal transduction events triggered by the activation of SLAM family receptors in different cell types.

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Classical MHC expression by DP thymocytes impairs the selection of non-classical MHC restricted innate-like T cells

Nature Communications ◽

10.1038/s41467-021-22589-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hristo Georgiev ◽

Changwei Peng ◽

Matthew A. Huggins ◽

Stephen C. Jameson ◽

Kristin A. Hogquist

Keyword(s):

T Cells ◽

Epithelial Cells ◽

Cell Types ◽

Inkt Cells ◽

Mhc I ◽

Mait Cells ◽

Mhc Molecules ◽

Mhc Ii ◽

Different Cell Types ◽

Selection Of

AbstractConventional T cells are selected by peptide-MHC expressed by cortical epithelial cells in the thymus, and not by cortical thymocytes themselves that do not express MHC I or MHC II. Instead, cortical thymocytes express non-peptide presenting MHC molecules like CD1d and MR1, and promote the selection of PLZF+ iNKT and MAIT cells, respectively. Here, we report an inducible class-I transactivator mouse that enables the expression of peptide presenting MHC I molecules in different cell types. We show that MHC I expression in DP thymocytes leads to expansion of peptide specific PLZF+ innate-like (PIL) T cells. Akin to iNKT cells, PIL T cells differentiate into three functional effector subsets in the thymus, and are dependent on SAP signaling. We demonstrate that PIL and NKT cells compete for a narrow niche, suggesting that the absence of peptide-MHC on DP thymocytes facilitates selection of non-peptide specific lymphocytes.

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ProtAnno, an Automated Cell Type Annotation Tool for Single Cell Proteomics Data that Integrates Information from Multiple Reference Sources

10.1101/2021.09.13.460162 ◽

2021 ◽

Author(s):

Wenxuan Deng ◽

Biqing Zhu ◽

Seyoung Park ◽

Tomokazu S. Sumida ◽

Avraham Unterman ◽

...

Keyword(s):

Single Cell ◽

Single Cells ◽

Earth Metal ◽

Cell Types ◽

Specific Cell ◽

Cell Type ◽

Proteomics Data ◽

Data Annotation ◽

Different Cell Types ◽

Unique Molecular Identifier

Compared with sequencing-based global genomic profiling, cytometry labels targeted surface markers on millions of cells in parallel either by conjugated rare earth metal particles or Unique Molecular Identifier (UMI) barcodes. Correct annotation of these cells to specific cell types is a key step in the analysis of these data. However, there is no computational tool that automatically annotates single cell proteomics data for cell type inference. In this manuscript, we propose an automated single cell proteomics data annotation approach called ProtAnno to facilitate cell type assignments without laborious manual gating. ProtAnno is designed to incorporate information from annotated single cell RNA-seq (scRNA-seq), CITE-seq, and prior data knowledge (which can be imprecise) on biomarkers for different cell types. We have performed extensive simulations to demonstrate the accuracy and robustness of ProtAnno. For several single cell proteomics datasets that have been manually labeled, ProtAnno was able to correctly label most single cells. In summary, ProtAnno offers an accurate and robust tool to automate cell type annotations for large single cell proteomics datasets, and the analysis of such annotated cell types can offer valuable biological insights.

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Single nucleus transcriptomic analysis of human dorsal root ganglion neurons

10.1101/2021.07.02.450845 ◽

2021 ◽

Author(s):

Minh Q Nguyen ◽

Lars J von Buchholtz ◽

Ashlie N Reker ◽

Nicholas J.P. Ryba ◽

Steve Davidson

Keyword(s):

Dorsal Root ◽

Somatosensory System ◽

Cell Types ◽

Dorsal Root Ganglion Neurons ◽

Sensory Function ◽

Specific Cell ◽

Drg Neurons ◽

Expression Of Genes ◽

Somatosensory Neurons ◽

Ganglion Neurons

Somatosensory neurons with cell bodies in the dorsal root ganglia (DRG) project to the skin, muscles, bones, and viscera to detect touch and temperature as well as to mediate proprioception and many types of interoception. In addition, the somatosensory system conveys the clinically relevant noxious sensations of pain and itch. Here we used single nuclear transcriptomics to characterize the classes of human DRG neurons that detect these diverse types of stimuli. Notably, multiple types of human DRG neurons have transcriptomic features that resemble their mouse counterparts although expression of genes considered important for sensory function often differed between species. More unexpectedly, we demonstrated that several classes of mouse neurons have no direct equivalents in humans and human specific cell-types were also identified. This dataset should serve as a valuable resource for the community, for example as means of focusing translational efforts on molecules with conserved expression across species.

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The Endocannabinoid System in Glial Cells and Their Profitable Interactions to Treat Epilepsy: Evidence from Animal Models

International Journal of Molecular Sciences ◽

10.3390/ijms222413231 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13231

Author(s):

Jon Egaña-Huguet ◽

Edgar Soria-Gómez ◽

Pedro Grandes

Keyword(s):

Glial Cells ◽

Endocannabinoid System ◽

Cell Types ◽

Specific Cell ◽

Neuronal Viability ◽

Wide Range ◽

Novel Target ◽

Different Cell Types ◽

The Impact

Epilepsy is one of the most common neurological conditions. Yearly, five million people are diagnosed with epileptic-related disorders. The neuroprotective and therapeutic effect of (endo)cannabinoid compounds has been extensively investigated in several models of epilepsy. Therefore, the study of specific cell-type-dependent mechanisms underlying cannabinoid effects is crucial to understanding epileptic disorders. It is estimated that about 100 billion neurons and a roughly equal number of glial cells co-exist in the human brain. The glial population is in charge of neuronal viability, and therefore, their participation in brain pathophysiology is crucial. Furthermore, glial malfunctioning occurs in a wide range of neurological disorders. However, little is known about the impact of the endocannabinoid system (ECS) regulation over glial cells, even less in pathological conditions such as epilepsy. In this review, we aim to compile the existing knowledge on the role of the ECS in different cell types, with a particular emphasis on glial cells and their impact on epilepsy. Thus, we propose that glial cells could be a novel target for cannabinoid agents for treating the etiology of epilepsy and managing seizure-like disorders.

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Filopodia rotate and coil by actively generating twist in their actin shaft

10.21203/rs.3.rs-81906/v1 ◽

2020 ◽

Author(s):

Natascha Leijnse ◽

Younes Barooji ◽

Bram Verhagen ◽

Lena Wullkopf ◽

Janine Erler ◽

...

Keyword(s):

Cell Types ◽

Narrow Channel ◽

Eukaryotic Cell ◽

General Mechanism ◽

Specific Cell ◽

Filamentous Actin ◽

Cell Matrix ◽

Matrix Interactions ◽

Cell Matrix Interactions ◽

Different Cell Types

Abstract Filopodia are actin-rich structures, present on the surface of practically every known eukaryotic cell. These structures play a pivotal role in specific cell-cell and cell-matrix interactions by allowing cells to explore their environment, generate mechanical forces, perform chemical signaling, or convey signals via intercellular tunneling nano-bridges. The dynamics of filopodia appear quite complex as they exhibit a rich behavior of buckling, pulling, length and shape changes. Here, we find that filopodia additionally explore their 3D extracellular space by combining growth and shrinking with axial twisting and buckling of their actin rich core. Importantly, we show the rotational dynamics of the filamentous actin inside filopodia for a range of highly distinct and cognate cell types spanning from earliest development to highly differentiated tissue cells. Non-equilibrium physical modeling of actin and myosin confirm that twist, and hence rotation, is an emergent phenomenon of active filaments confined in a narrow channel which points to a generic mechanism present in all cells. Our measurements confirm that filopodia exert traction forces and form helical buckles in a range of different cell types that can be ascribed to accumulation of sufficient twist. These results lead us to conclude that activity induced twisting of the actin shaft is a general mechanism underlying fundamental functions of filopodia

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Single-Cell Sequencing Applications in the Inner Ear

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.637779 ◽

2021 ◽

Vol 9 ◽

Author(s):

Mingxuan Wu ◽

Mingyu Xia ◽

Wenyan Li ◽

Huawei Li

Keyword(s):

Gene Expression ◽

Single Cell ◽

Inner Ear ◽

Signaling Pathways ◽

Cell Types ◽

Specific Cell ◽

Tissue Heterogeneity ◽

Single Cell Sequencing ◽

Cell Groups ◽

Different Cell Types

Genomics studies face specific challenges in the inner ear due to the multiple types and limited amounts of inner ear cells that are arranged in a very delicate structure. However, advances in single-cell sequencing (SCS) technology have made it possible to analyze gene expression variations across different cell types as well as within specific cell groups that were previously considered to be homogeneous. In this review, we summarize recent advances in inner ear research brought about by the use of SCS that have delineated tissue heterogeneity, identified unknown cell subtypes, discovered novel cell markers, and revealed dynamic signaling pathways during development. SCS opens up new avenues for inner ear research, and the potential of the technology is only beginning to be explored.

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