Summary
Interferon‐inducible transmembrane (IFITM) proteins are a family of small homologous proteins, localized in the plasma and endolysosomal membranes, which confer cellular resistance to many ...viruses. In addition, several distinct functions have been associated with different IFITM family members, including germ cell specification (IFITM1–IFITM3), osteoblast function and bone mineralization (IFITM5) and immune functions (IFITM1–3, IFITM6). IFITM1–3 are expressed by T cells and recent experiments have shown that the IFITM proteins are directly involved in adaptive immunity and that they regulate CD4+ T helper cell differentiation in a T‐cell‐intrinsic manner. Here we review the role of the IFITM proteins in T‐cell differentiation and function.
Recent studies have identified new T‐cell‐intrinsic roles for the IFITM family in T helper differentiation and atopic and inflammatory disease, which are independent of their functions in cellular resistance to viral infection.
Testis Development Mäkelä, Juho-Antti; Koskenniemi, Jaakko J; Virtanen, Helena E ...
Endocrine reviews,
2019-August, Letnik:
40, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Abstract
Production of sperm and androgens is the main function of the testis. This depends on normal development of both testicular somatic cells and germ cells. A genetic program initiated from the ...Y chromosome gene sex-determining region Y (SRY) directs somatic cell specification to Sertoli cells that orchestrate further development. They first guide fetal germ cell differentiation toward spermatogenic destiny and then take care of the full service to spermatogenic cells during spermatogenesis. The number of Sertoli cells sets the limits of sperm production. Leydig cells secrete androgens that determine masculine development. Testis development does not depend on germ cells; that is, testicular somatic cells also develop in the absence of germ cells, and the testis can produce testosterone normally to induce full masculinization in these men. In contrast, spermatogenic cell development is totally dependent on somatic cells. We herein review germ cell differentiation from primordial germ cells to spermatogonia and development of the supporting somatic cells. Testicular descent to scrota is necessary for normal spermatogenesis, and cryptorchidism is the most common male birth defect. This is a mild form of a disorder of sex differentiation. Multiple genetic reasons for more severe forms of disorders of sex differentiation have been revealed during the last decades, and these are described along with the description of molecular regulation of testis development.
It is known that excessive adipogenesis contributes to osteoporosis, suggesting that trans-differentiation of adipogenic committed preadipocytes into osteoblasts may be a potential therapeutical ...approach for osteoporosis. We explored whether bone morphogenic protein 9 (BMP9) could induce 3T3-L1 preadipocytes to trans-differentiate into osteoblasts. BMP9 effectively increased expression of osteogenic markers and promoted mineralization in preadipocytes. However, BMP9 also led to adipogenic differentiation of preadipocytes, as evidenced by increased lipid accumulation and up-regulation of adipogenic transcription factors. In order to regulate the switch between osetogenesis and adipogenesis, we evaluated the effect of all-trans retinoic acid (ATRA) on BMP9-induced differentiation of preadipocytes. We found that ATRA enhanced BMP9-induced osteogenic differentiation and blocked BMP9-induced adipogenic differentiation both in vitro and in vivo. Mechanistically, ATRA was shown to elevate BMP9 expression and activate BMP/Smad signaling. Additionally, BMP9 and ATRA exerted a synergistic effect on activation of Wnt/β-catenin signaling. Knockdown of β-catenin abolished the stimulatory effect of ATRA on BMP9-induced alkaline phosphatase activity and reversed the inhibitory effect of ATRA on BMP9-induced adipogenesis in preadipocytes. Furthermore, ATRA and BMP9 synergistically repressed glycogen synthase kinase 3β (GSK3β) activity and promoted Akt phosphorylation, and inhibited expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) that antagonizes phosphatidylinositol-3-kinase (PI3K) function, suggesting that Wnt/β-catenin signaling was activated at least partly through PI3K/Akt/GSK3β pathway. Collectively, ATRA mediated BMP9-induced osteogenic or adipogenic differentiation of 3T3-L1 preadipocytes by BMP/Smad and Wnt/β-catenin signaling. The combination of BMP9 and ATRA may be explored as an effective therapeutic strategy for osteoporosis.
Microglia, the innate immune cells of the brain, have recently been removed from the position of mere sentinels and promoted to the role of active sculptors of developing circuits and cells. ...Alongside their functions in normal brain development, microglia coordinate sexual differentiation of the brain, a set of processes which vary by region and endpoint like that of microglia function itself. In this review, we highlight the ways microglia are both targets and drivers of brain sexual differentiation. We examine the factors that may drive sex differences in microglia, with a special focus on how changing microenvironments in the developing brain dictate microglia phenotypes and discuss how their diverse functions sculpt lasting sex‐specific changes in the brain. Finally, we consider how sex‐specific early life environments contribute to epigenetic programming and lasting sex differences in microglia identity.
Main Points
The process of sexual differentiation generates sex‐specific microenvironments in brain development. Microenvironmental signals drive sex‐specific microglia functions to sculpt brain development and behavior. Sex differences in microglia drive sex‐specific changes in neuronal and astrocytic functions that endure throughout the lifespan.
The four known ID proteins (ID1-4, Inhibitor of Differentiation) share a homologous helix loop helix (HLH) domain and act as dominant negative regulators of basic-HLH transcription factors. ID ...proteins also interact with many non-bHLH proteins in complex networks. The expression of ID proteins is increasingly observed in many cancers. Whereas ID-1, ID-2 and ID-3, are generally considered as tumor promoters, ID4 on the contrary has emerged as a tumor suppressor. In this study we demonstrate that ID4 heterodimerizes with ID-1, -2 and -3 and promote bHLH DNA binding, essentially acting as an inhibitor of inhibitors of differentiation proteins. Interaction of ID4 was observed with ID1, ID2 and ID3 that was dependent on intact HLH domain of ID4. Interaction with bHLH protein E47 required almost 3 fold higher concentration of ID4 as compared to ID1. Furthermore, inhibition of E47 DNA binding by ID1 was restored by ID4 in an EMSA binding assay. ID4 and ID1 were also colocalized in prostate cancer cell line LNCaP. The alpha helix forming alanine stretch N-terminal, unique to HLH ID4 domain was required for optimum interaction. Ectopic expression of ID4 in DU145 prostate cancer line promoted E47 dependent expression of CDKNI p21. Thus counteracting the biological activities of ID-1, -2 and -3 by forming inactive heterodimers appears to be a novel mechanism of action of ID4. These results could have far reaching consequences in developing strategies to target ID proteins for cancer therapy and understanding biologically relevant ID-interactions.
•ID4 acts as inhibitor of Inhibitor of Differentiation (IDs 1, 2 and 3) proteins.•ID4 hetero-dimerizes and neutralizes the oncogenic activity of IDs 1, 2 and 3.•The alpha helix forming alanine stretch in ID4 is required for protein interactions.•The proposed mechanism supports the role of ID4 as tumor suppressor.
By solving the Maxwell's equations in Fourier space, we find that the cross-polarized component of the dipole scattering field can be written as the second-order spatial differentiation of the ...copolarized component. This differential operation can be regarded as intrinsic which naturally arises as consequence of the transversality of electromagnetic fields. By introducing the intrinsic spatial differentiation into heralded single-photon microscopy imaging technique, it makes the structure of pure-phase object clearly visible at low photon level, avoiding any biophysical damages to living cells. Based on the polarization entanglement, the switch between dark-field imaging and bright-field imaging is remotely controlled in the heralding arm. This research enriches both fields of optical analog computing and quantum microscopy, opening a promising route toward a nondestructive imaging of living biological systems.
Pulmonary arterial hypertension is a disease of proliferative vascular occlusion that is strongly linked to mutations in
-the gene encoding the BMPR-II (BMP bone morphogenetic protein type II ...receptor). The endothelial-selective BMPR-II ligand, BMP9, reverses disease in animal models of pulmonary arterial hypertension and suppresses the proliferation of healthy endothelial cells. However, the impact of
loss on the antiproliferative actions of BMP9 has yet to be assessed. Approach and Results: BMP9 suppressed proliferation in blood outgrowth endothelial cells from healthy control subjects but increased proliferation in blood outgrowth endothelial cells from pulmonary arterial hypertension patients with
mutations. This shift from growth suppression to enhanced proliferation was recapitulated in control human pulmonary artery endothelial cells following siRNA-mediated
silencing, as well as in mouse pulmonary endothelial cells isolated from endothelial-conditional
knockout mice (
). BMP9-induced proliferation was not attributable to altered metabolic activity or elevated TGFβ (transforming growth factor beta) signaling but was linked to the prolonged induction of the canonical BMP target
in the context of
loss. In vivo, daily BMP9 administration to neonatal mice impaired both retinal and lung vascular patterning in control mice (
) but had no measurable effect on mice bearing a heterozygous endothelial
deletion (
) and caused excessive angiogenesis in both vascular beds for
mice.
loss reverses the endothelial response to BMP9, causing enhanced proliferation. This finding has potential implications for the proposed translation of BMP9 as a treatment for pulmonary arterial hypertension and suggests the need for focused patient selection in clinical trials.
Since their serendipitous discovery in nematodes, microRNAs (miRNAs) have emerged as key regulators of biological processes in animals. These small RNAs form complex networks that regulate cell ...differentiation, development and homeostasis. Deregulation of miRNA function is associated with an increasing number of human diseases, particularly cancer. Recent discoveries have expanded our understanding of the control of miRNA function. Here, we review the mechanisms that modulate miRNA activity, stability and cellular localization through alternative processing and maturation, sequence editing, post-translational modifications of Argonaute proteins, viral factors, transport from the cytoplasm and regulation of miRNA-target interactions. We conclude by discussing intriguing, unresolved research questions.
CD69 is a membrane‐bound, type II C‐lectin receptor. It is a classical early marker of lymphocyte activation due to its rapid appearance on the surface of the plasma membrane after stimulation. CD69 ...is expressed by several subsets of tissue resident immune cells, including resident memory T (TRM) cells and gamma delta (γδ) T cells, and is therefore considered a marker of tissue retention. Recent evidence has revealed that CD69 regulates some specific functions of selected T‐cell subsets, determining the migration‐retention ratio as well as the acquisition of effector or regulatory phenotypes. Specifically, CD69 regulates the differentiation of regulatory T (Treg) cells as well as the secretion of IFN‐γ, IL‐17, and IL‐22. The identification of putative CD69 ligands, such as Galectin‐1 (Gal‐1), suggests that CD69‐induced signaling can be regulated not only during cognate contacts between T cells and antigen‐presenting cells in lymphoid organs, but also in the periphery, where cytokines and other metabolites control the final outcome of the immune response. Here, we will discuss new aspects of the molecular signaling mediated by CD69 and its involvement in the metabolic reprogramming regulating TH‐effector lineages.
CD69 associates to LAT1 and controls its plasma membrane expression and amino acid transporter activity in T lymphocytes.
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