Reduced SPAG17 Expression in Systemic Sclerosis Triggers Myofibroblast Transition and Drives Fibrosis.

Systemic sclerosis (SSc) is a clinically heterogeneous fibrotic disease with no effective treatment. Myofibroblasts are responsible for unresolving synchronous skin and internal organ fibrosis in SSc, but the drivers of sustained myofibroblast activation remain poorly understood. Using unbiased transcriptome analysis of skin biopsies, we identified the downregulation of SPAG17 in multiple independent cohorts of patients with SSc, and by orthogonal approaches, we observed a significant negative correlation between SPAG17 and fibrotic gene expression. Fibroblasts and endothelial cells explanted from SSc skin biopsies showed reduced chromatin accessibility at the SPAG17 locus. Remarkably, mice lacking Spag17 showed spontaneous skin fibrosis with increased dermal thickness, collagen deposition and stiffness, and altered collagen fiber alignment. Knockdown of SPAG17 in human and mouse fibroblasts and microvascular endothelial cells was accompanied by spontaneous myofibroblast transformation and markedly heightened sensitivity to profibrotic stimuli. These responses were accompanied by constitutive TGF-ß pathway activation. Thus, we discovered impaired expression of SPAG17 in SSc and identified, to our knowledge, a previously unreported cell-intrinsic role for SPAG17 in the negative regulation of fibrotic responses. These findings shed fresh light on the pathogenesis of SSc and may inform the search for innovative therapies for SSc and other fibrotic conditions through SPAG17 signaling.

Sperm Differentiation: The Role of Trafficking of Proteins.

Sperm differentiation encompasses a complex sequence of morphological changes that takes place in the seminiferous epithelium. In this process, haploid round spermatids undergo substantial structural and functional alterations, resulting in highly polarized sperm. Hallmark changes during the differentiation process include the formation of new organelles, chromatin condensation and nuclear shaping, elimination of residual cytoplasm, and assembly of the sperm flagella. To achieve these transformations, spermatids have unique mechanisms for protein trafficking that operate in a coordinated fashion. Microtubules and filaments of actin are the main tracks used to facilitate the transport mechanisms, assisted by motor and non-motor proteins, for delivery of vesicular and non-vesicular cargos to specific sites. This review integrates recent findings regarding the role of protein trafficking in sperm differentiation. Although a complete characterization of the interactome of proteins involved in these temporal and spatial processes is not yet known, we propose a model based on the current literature as a framework for future investigations.

The Primary Cilium: Emerging Role as a Key Player in Fibrosis.

PURPOSE OF REVIEW: The myofibroblast is the culprit in the pathogenesis of fibrosis in systemic sclerosis (SSc). Activation of morphogen signaling pathways has been shown to be critically involved in organ fibrosis. Remarkably, the cellular receptors and key molecules from these signaling pathways are localized in the primary cilium. The primary cilium is a unique cellular organelle present in virtually all cells. This article summarizes recent studies evaluating the association between primary cilia and morphogen signaling driving myofibroblast transition and subsequent fibrosis. RECENT FINDINGS: Emerging observations implicate dysfunctional primary cilia in fibrosis in many different tissues and organs. Primary cilia seem to be necessary for the initiation of the transition and sustained activation of myofibroblasts. We summarize recent progress in this field and propose the primary cilium as a potential mediator of fibrosis pathogenesis in SSc. Understanding the contributions of primary cilia in fibrosis may ultimately inform the development of entirely new approaches for fibrosis prevention and treatment.

SPAG17 Is Required for Male Germ Cell Differentiation and Fertility.

Spag17 encodes a protein present in the axoneme central pair complex of motile cilia and flagella. A mutation in this gene has been reported to be associated with infertility caused by defects in sperm motility. Here, we report that Spag17 knockout mice are infertile because of a severe defect in spermatogenesis. The histological evaluation of testis sections from mutant mice revealed seminiferous tubules with spermatogenesis arrested at the spermatid stage and cell debris in the cauda epididymis. The few sperm collected from the cauda epididymis were immotile and displayed abnormal tail and head morphology. Immunofluorescence analysis of Spag17 knockout germ cells showed spermatids with abnormally long manchette structures and morphological defects in the head. Electron microscopy showed altered manchette microtubules, reduced chromatin condensation, irregular nuclear shape, and detached acrosomes. Additionally, the transport of proteins (Pcdp1 and IFT20) along the manchette microtubules was disrupted in the knockout elongating spermatids. Our results show for the first time that Spag17 is essential for normal manchette structure, protein transport, and formation of the sperm head and flagellum, in addition to its role in sperm motility.

Genome Sequences of Chancellor, Mitti, and Wintermute, Three Subcluster K4 Phages Isolated Using Mycobacterium smegmatis mc2155.

Mycobacteriophages Chancellor, Mitti, and Wintermute infect Mycobacterium smegmatis mc2155 and are closely related to phages Cheetobro and Fionnbharth in subcluster K4. Genome sizes range from 57,697 bp to 58,046 bp. Phages are predicted to be temperate and to infect the pathogen Mycobacterium tuberculosis.