Molecular Regulatory Mechanism of Exocytosis in the Salivary Glands

Suzuki, Akiko; Iwata, Junichi

doi:10.3390/ijms19103208

Cited by 15 publications

(10 citation statements)

References 150 publications

(187 reference statements)

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“…Interestingly, we observed downregulation of a number of genes belonging to the Ras superfamily of GTPases (RAB GTPases). RAB GTPases play critical roles in exocytosis and membrane trafficking including vesicle formation, docking and membrane fusion, all vital functions necessary for proper saliva secretion ( 55 ). More specifically, we observed reduced gene expression levels of Rabac1 and Rab6b in the salivary glands of SS mice compared to control animals ( Supplementary Figure S4 ).…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic and Single-Cell Analysis Reveals Regulatory Networks and Cellular Heterogeneity in Mouse Primary Sjögren’s Syndrome Salivary Glands

et al. 2021

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Sjögren’s Syndrome (SS) is a chronic autoimmune disease of unknown etiology which primarily affects the salivary and lacrimal glands resulting in the loss of secretory function. Treatment options for SS have been hampered due to the lack of a better understanding of the underlying gene regulatory circuitry and the interplay between the myriad pathological cellular states that contribute to salivary gland dysfunction. To better elucidate the molecular nature of SS, we have performed RNA-sequencing analysis of the submandibular glands (SMG) of a well-established primary Sjögren’s Syndrome (pSS) mouse model. Our comprehensive examination of global gene expression and comparative analyses with additional SS mouse models and human datasets, have identified a number of important pathways and regulatory networks that are relevant in SS pathobiology. To complement these studies, we have performed single-cell RNA sequencing to examine and identify the molecular and cellular heterogeneity of the diseased cell populations of the mouse SMG. Interrogation of the single-cell transcriptomes has shed light on the diversity of immune cells that are dysregulated in SS and importantly, revealed an activated state of the salivary gland epithelial cells that contribute to the global immune mediated responses. Overall, our broad studies have not only revealed key pathways, mediators and new biomarkers, but have also uncovered the complex nature of the cellular populations in the SMG that are likely to drive the progression of SS. These newly discovered insights into the underlying molecular mechanisms and cellular states of SS will better inform targeted therapeutic discoveries.

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Section: Resultsmentioning

confidence: 99%

Transcriptomic and Single-Cell Analysis Reveals Regulatory Networks and Cellular Heterogeneity in Mouse Primary Sjögren’s Syndrome Salivary Glands

et al. 2021

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“…Ultrastructurally, large secretory granules were accumulated in the acini of diabetes SMGs, and more were scattered in the acini of diabetes PGs. Proteins are the main component of secretory granules and their secretion is a dynamic process comprising synthesis, transport, and secretion (Suzuki and Iwata, 2018). Here, the docked secretory granules in diabetes SMG and PG suggested that the process of secretion is somehow impaired in diabetic condition.…”

Section: Discussionmentioning

confidence: 99%

Disruption of tight junctions contributes to hyposalivation of salivary glands in a mouse model of type 2 diabetes

et al. 2020

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Tight junction (TJ) plays an important role in regulating paracellular fluid transport in salivary glands; however, little is known about the involvement of TJs in diabetes salivary glands. This study aimed to investigate the alterations of TJs and their possible contribution in diabetes‐induced hyposalivation. Here, we observed that the morphologies of submandibular glands (SMGs) were impaired, characterized by enlarged acini accumulation with giant secretory granules, which were significantly reduced in atrophic ducts in SMGs of db/db mice, a spontaneous model of type‐2 diabetes. However, the secretory granules were increased and scattered in the acini of diabetes parotid glands (PGs). Other ultrastructural damages including swollen mitochondria, expansive endoplasmic reticulum, and autophagosomes were observed in the diabetes group. The levels of TJ proteins including claudin‐1 (Cldn1) and claudin‐3 (Cldn3) were increased, whereas those of claudin‐4 (Cldn4), occludin (Ocln), and zonula occludens‐1 (ZO‐1) were decreased in SMGs of db/db mice. Higher Cldn1 and Cldn3 and lower claudin‐10 (Cldn10) and Ocln levels were observed in PGs of diabetes mice. Taken together, the structures of SMGs and PGs were impaired in diabetes mice, and the disruption of TJ integrity in both SMGs and PGs may contribute to diabetes‐induced hyposalivation.

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“…The three pairs of major (submandibular, parotid and sublingual) and minor salivary glands secrete saliva in the mouth. Saliva presents diverse functions, including lubrication, initiation of digestion, and immunity [18]. It is a biofluid rich in water, ions, and several protein groups, including mucins, which are proteins glycosylated, and most have high sialic acid content [19].…”

Section: Salivary Glands and Salivamentioning

confidence: 99%