Species-specific oscillation periods of human and mouse segmentation clocks are due to cell autonomous differences in biochemical reaction parameters

Abstract Genetic variations of TREM2 have been implicated as a risk factor of Alzheimer’s disease (AD). Recent studies suggest that the loss of TREM2 function compromises microglial responses to the accumulation of amyloid beta. Previously, we found that exon 3 of TREM2 is an alternative exon whose skipping leads to a reduction in full-length TREM2 protein by inducing nonsense-mediated mRNA decay. Here, we aimed to identify factors regulating TREM2 splicing. Using a panel of RNA-binding proteins, we found that exon 3 skipping of TREM2 was promoted by two paralogous proteins, CELF1 and CELF2, which were both linked previously with risk loci of AD. Although the overexpression of both CELF1 and CELF2 enhanced exon 3 skipping, only CELF2 reduced the expression of full-length TREM2 protein. Notably, the TREM2 ortholog in the green monkey, but not in the mouse, showed alternative splicing of exon 3 like human TREM2. Similarly, splicing regulation of exon 3 by CELF1/2 was found to be common to humans and monkeys. Using chimeric minigenes of human and mouse TREM2, we mapped a CELF-responsive sequence within intron 3 of human TREM2. Collectively, our results revealed a novel regulatory factor of TREM2 expression and highlighted a species-dependent difference of its regulation.

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Differential Activation of Human and Mouse Toll-Like Receptor 4 by the Adjuvant Candidate LpxL1 of Neisseria meningitidis

Infection and Immunity ◽

10.1128/iai.00005-08 ◽

2008 ◽

Vol 76 (8) ◽

pp. 3801-3807 ◽

Cited By ~ 56

Author(s):

Liana Steeghs ◽

A. Marijke Keestra ◽

Andries van Mourik ◽

Heli Uronen-Hansson ◽

Peter van der Ley ◽

...

Keyword(s):

Neisseria Meningitidis ◽

Lipid A ◽

Vaccine Development ◽

Meningococcal Vaccine ◽

Toll Like Receptor ◽

Wild Type ◽

Toll Like Receptor 4 ◽

Species Specific ◽

Human And Mouse ◽

Dc Maturation

ABSTRACT Neisseria meningitidis LpxL1 lipopolysaccharide (LPS) bearing penta-acylated lipid A is considered a promising adjuvant candidate for inclusion in future N. meningitidis vaccines, as it elicits a markedly reduced endotoxic response in human macrophages relative to that in wild-type (hexa-acylated) LPS, while it is an equally effective adjuvant in mice. As dendritic cells (DC) and Toll-like receptors (TLR) are regarded as central mediators in the initiation of an immune response, here we evaluated the ability of LpxL1 LPS to mature and to activate human DC and examined its TLR4-/MD-2-activating properties. Unexpectedly, purified LpxL1 LPS displayed minimal human DC-stimulating properties compared to wild-type LPS. Although whole bacteria induced DC maturation and activation irrespective of their type of LPS, the LpxL1 mutant failed to activate the human recombinant TLR4/MD-2 complex expressed in HeLa cells. Similarly, purified LpxL1 LPS was unable to activate human TLR4/MD-2 and it even acted as an antagonist of wild-type LPS. Both wild-type and LpxL1 LPSs activated the murine TLR4/MD-2 complex, consistent with their abilities to induce maturation and activation of murine DC. Assays with cells transfected with different combinations of human and murine TLR4 and MD-2 indicated that TLR4 was a more-major determinant of the LPS response than MD-2. The species-specific activation of the TLR4/MD-2 complex by LpxL1 LPS may have an impact on the use of LpxL1 LPS as an adjuvant and the use of murine immunization models in human meningococcal vaccine development.

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Differential CYP 2D6 Metabolism Alters Primaquine Pharmacokinetics

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00015-15 ◽

2015 ◽

Vol 59 (4) ◽

pp. 2380-2387 ◽

Cited By ~ 42

Author(s):

Brittney M. J. Potter ◽

Lisa H. Xie ◽

Chau Vuong ◽

Jing Zhang ◽

Ping Zhang ◽

...

Keyword(s):

Enzyme Activity ◽

Antimalarial Activity ◽

Wild Type ◽

Phenolic Metabolites ◽

Species Specific ◽

Human And Mouse ◽

Different Levels ◽

Cyp 2D6

ABSTRACTPrimaquine (PQ) metabolism by the cytochrome P450 (CYP) 2D family of enzymes is required for antimalarial activity in both humans (2D6) and mice (2D). Human CYP 2D6 is highly polymorphic, and decreased CYP 2D6 enzyme activity has been linked to decreased PQ antimalarial activity. Despite the importance of CYP 2D metabolism in PQ efficacy, the exact role that these enzymes play in PQ metabolism and pharmacokinetics has not been extensively studiedin vivo. In this study, a series of PQ pharmacokinetic experiments were conducted in mice with differential CYP 2D metabolism characteristics, including wild-type (WT), CYP 2D knockout (KO), and humanized CYP 2D6 (KO/knock-in [KO/KI]) mice. Plasma and liver pharmacokinetic profiles from a single PQ dose (20 mg/kg of body weight) differed significantly among the strains for PQ and carboxy-PQ. Additionally, due to the suspected role of phenolic metabolites in PQ efficacy, these were probed using reference standards. Levels of phenolic metabolites were highest in mice capable of metabolizing CYP 2D6 substrates (WT and KO/KI 2D6 mice). PQ phenolic metabolites were present in different quantities in the two strains, illustrating species-specific differences in PQ metabolism between the human and mouse enzymes. Taking the data together, this report furthers understanding of PQ pharmacokinetics in the context of differential CYP 2D metabolism and has important implications for PQ administration in humans with different levels of CYP 2D6 enzyme activity.

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Differential Expression of a Cutaneous Corticotropin-Releasing Hormone System

Endocrinology ◽

10.1210/en.2003-0851 ◽

2004 ◽

Vol 145 (2) ◽

pp. 941-950 ◽

Cited By ~ 126

Author(s):

Andrzej Slominski ◽

Alexander Pisarchik ◽

Desmond J. Tobin ◽

Joseph E. Mazurkiewicz ◽

Jacobo Wortsman

Keyword(s):

Human Skin ◽

Expression Patterns ◽

Mouse Skin ◽

Hair Follicles ◽

Dermal Fibroblasts ◽

Preferential Expression ◽

Eccrine Glands ◽

Species Specific ◽

Skin Function ◽

Human And Mouse

Abstract We completed the mapping of a cutaneous CRH signaling system in two species with widely different determinants of skin functions, humans and mice. In human skin, the CRH receptor (CRH-R) 1 was expressed in all major cellular populations of epidermis, dermis, and subcutis with CRH-R1α being the most prevalent isoform. The CRH-R2 gene was expressed solely in hair follicle keratinocytes and papilla fibroblasts, whereas CRH-R2 antigen was localized predominantly in hair follicles, sebaceous and eccrine glands, muscle and blood vessels. In mouse skin, the CRH-R2 gene and protein were widely expressed in all cutaneous compartments and in cultured normal and malignant melanocytes. CRH-binding protein mRNA was present in dermal fibroblasts, melanoma cells, and sc fat of human skin and undetectable in mouse skin. The urocortin II gene was expressed equally in mouse and human skin. Taken together with our previous investigations, the present studies document the preferential expression of CRH-R1 in human skin, which mirrors CRH-R2 expression patterns in human and mouse skin. They are likely reflecting different functional activities of human and mouse skin. The adnexal location of CRH-R2 suggests a role for the receptor in hair growth. The differential interspecies CRH signaling expression pattern probably reflects adaptation to species-specific skin function determinants.

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Species Selectivity of Mixed-Lineage Leukemia/Trithorax and HCF Proteolytic Maturation Pathways

Molecular and Cellular Biology ◽

10.1128/mcb.00769-07 ◽

2007 ◽

Vol 27 (20) ◽

pp. 7063-7072 ◽

Cited By ~ 40

Author(s):

Francesca Capotosti ◽

James J.-D. Hsieh ◽

Winship Herr

Keyword(s):

Proteolytic Processing ◽

Mixed Lineage Leukemia ◽

Regulatory Activity ◽

Site Specific ◽

Trithorax Group ◽

Species Specific ◽

Simplex Virus ◽

Host Cell Factor 1 ◽

Human And Mouse

ABSTRACT Site-specific proteolytic processing plays important roles in the regulation of cellular activities. The histone modification activity of the human trithorax group mixed-lineage leukemia (MLL) protein and the cell cycle regulatory activity of the cell proliferation factor herpes simplex virus host cell factor 1 (HCF-1) are stimulated by cleavage of precursors that generates stable heterodimeric complexes. MLL is processed by a protease called taspase 1, whereas the precise mechanisms of HCF-1 maturation are unclear, although they are known to depend on a series of sequence repeats called HCF-1PRO repeats. We demonstrate here that the Drosophila homologs of MLL and HCF-1, called Trithorax and dHCF, are both cleaved by Drosophila taspase 1. Although highly related, the human and Drosophila taspase 1 proteins display cognate species specificity. Thus, human taspase 1 preferentially cleaves MLL and Drosophila taspase 1 preferentially cleaves Trithorax, consistent with coevolution of taspase 1 and MLL/Trithorax proteins. HCF proteins display even greater species-specific divergence in processing: whereas dHCF is cleaved by the Drosophila taspase 1, human and mouse HCF-1 maturation is taspase 1 independent. Instead, human and Xenopus HCF-1PRO repeats are cleaved in vitro by a human proteolytic activity with novel properties. Thus, from insects to humans, HCF proteins have conserved proteolytic maturation but evolved different mechanisms.

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Heterophilic and homophilic cadherin interactions in intestinal intermicrovillar links are species dependent

PLoS Biology ◽

10.1371/journal.pbio.3001463 ◽

2021 ◽

Vol 19 (12) ◽

pp. e3001463

Author(s):

Michelle E. Gray ◽

Zachary R. Johnson ◽

Debadrita Modak ◽

Elakkiya Tamilselvan ◽

Matthew J. Tyska ◽

...

Keyword(s):

Binding Assays ◽

Structural Determinants ◽

Calcium Dependent ◽

Dependent Cell ◽

Adhesive Interactions ◽

Species Specific ◽

Homophilic Adhesion ◽

Cell Adhesion Proteins ◽

Human And Mouse ◽

Cadherin Superfamily

Enterocytes are specialized epithelial cells lining the luminal surface of the small intestine that build densely packed arrays of microvilli known as brush borders. These microvilli drive nutrient absorption and are arranged in a hexagonal pattern maintained by intermicrovillar links formed by 2 nonclassical members of the cadherin superfamily of calcium-dependent cell adhesion proteins: protocadherin-24 (PCDH24, also known as CDHR2) and the mucin-like protocadherin (CDHR5). The extracellular domains of these proteins are involved in heterophilic and homophilic interactions important for intermicrovillar function, yet the structural determinants of these interactions remain unresolved. Here, we present X-ray crystal structures of the PCDH24 and CDHR5 extracellular tips and analyze their species-specific features relevant for adhesive interactions. In parallel, we use binding assays to identify the PCDH24 and CDHR5 domains involved in both heterophilic and homophilic adhesion for human and mouse proteins. Our results suggest that homophilic and heterophilic interactions involving PCDH24 and CDHR5 are species dependent with unique and distinct minimal adhesive units.

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Comparison of the central human and mouse platelet signaling cascade by systems biological analysis

10.21203/rs.3.rs-41477/v1 ◽

2020 ◽

Author(s):

Johannes Balkenhol ◽

Kristin V. Kaltdorf ◽

Elmina Mammadova-Bach ◽

Attila Braun ◽

Bernhard Nieswandt ◽

...

Keyword(s):

Molecular Mechanisms ◽

Interaction Network ◽

Human Platelets ◽

Fine Tuning ◽

Protein Levels ◽

Platelet Protein ◽

Thrombosis Research ◽

Platelet Signaling ◽

Species Specific ◽

Human And Mouse

Abstract Background Understanding the molecular mechanisms of platelet activation and aggregation is of high interest for basic and clinical hemostasis and thrombosis research. The central platelet protein interaction network is involved in major responses to exogenous factors. This is defined by systemsbiological pathway analysis as the central regulating signaling cascade of platelets (CC). Results The CC is systematically compared here between mouse and human and major differences were found. Genetic differences were analysed comparing orthologous human and mouse genes. We next analyzed different expression levels of mRNAs. Considering 4 mouse and 7 human high quality proteome data sets, we identified then those major mRNA expression differences (81%) which were supported by proteome data. CC is conserved regarding genetic completeness, but we observed major differences in mRNA and protein levels between both species. Looking at central interactors, human PLCB2, MMP9, BDNF, ITPR3 and SLC25A6 (always uniprot notation) show absence in all murine datasets. CC interactors GNG12, PRKCE and ADCY9 occur only in mice. Looking at the common proteins, TLN1, CALM3, PRKCB, APP, SOD2 and TIMP1 are higher abundant in human, whereas RASGRP2, ITGB2, MYL9, EIF4EBP1, ADAM17, ARRB2, CD9 and ZYX are higher abundant in mouse. Pivotal kinase SRC shows different regulation on mRNA and protein level as well as ADP receptor P2RY12. Conclusions Our results highlight species-specific differences in platelet signaling and points of specific fine-tuning in human platelets as well as murine-specific signalling differences.

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Species-specific segmentation clock periods are due to differential biochemical reaction speeds

Science ◽

10.1126/science.aba7668 ◽

2020 ◽

Vol 369 (6510) ◽

pp. 1450-1455 ◽

Cited By ~ 7

Author(s):

Mitsuhiro Matsuda ◽

Hanako Hayashi ◽

Jordi Garcia-Ojalvo ◽

Kumiko Yoshioka-Kobayashi ◽

Ryoichiro Kageyama ◽

...

Keyword(s):

Mathematical Model ◽

Time Scale ◽

Biochemical Parameters ◽

Core Gene ◽

Biochemical Reaction ◽

Segmentation Clock ◽

Human Segmentation ◽

The Core ◽

Mouse Cells ◽

Species Specific

Although mechanisms of embryonic development are similar between mice and humans, the time scale is generally slower in humans. To investigate these interspecies differences in development, we recapitulate murine and human segmentation clocks that display 2- to 3-hour and 5- to 6-hour oscillation periods, respectively. Our interspecies genome-swapping analyses indicate that the period difference is not due to sequence differences in the HES7 locus, the core gene of the segmentation clock. Instead, we demonstrate that multiple biochemical reactions of HES7, including the degradation and expression delays, are slower in human cells than they are in mouse cells. With the measured biochemical parameters, our mathematical model accounts for the two- to threefold period difference between the species. We propose that cell-autonomous differences in biochemical reaction speeds underlie temporal differences in development between species.

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