Biology subjects

Osipovich, A. B.

Publications and source records attributed to Osipovich, A. B..

3 recordsLinked to original sources

bioRxiv2022

Species-specific roles for the MAFA and MAFB transcription factors in regulatingislet β cell identity

Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet beta ({beta}) cells, characterized by inappropriate production of other islet cell-enriched hormones. Here we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in {beta} cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin (Gast)-positive cells generated under conditions of chronic hyperglycemia and obesity. A human {beta} cell line deficient in MAFB, but not one lacking MAFA, also produced a gastrin (GAST)-positive gene expression pattern. In addition, GAST was detected in human T2D {beta} cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a novel, species-specific role for MafA and MAFB in maintaining adult mouse and human {beta} cell identity, respectively, by repressing expression of Gast/GAST and other non-{beta} cell hormones.

cell biology↗

bioRxiv2022

The microtubule minus end-binding protein CAMSAP2 does not regulate microtubule dynamics in primary pancreatic β-cells but facilitates insulin secretion

Glucose stimulation induces the remodeling of microtubules in Islet {beta}-cells to potentiate glucose-stimulated insulin secretion. CAMSAP2 is a microtubule minus-end binding protein and is reported to stabilize and position microtubules in several non-{beta}-cells, such as human retinal pigment epithelium cells. In immortalized insulinoma MIN6 cells, CAMSAP2 binds to and forms short stretches at microtubule minus ends in the cytoplasm, which is consistent with the reported subcellular localization and functions of CAMSAP2 in non-{beta}-cells. Surprisingly, we found that CAMSAP2 expressed in primary islet {beta}-cells does not form short stretches in the cytoplasm, but instead is localized to the Golgi apparatus. This novel localization is specific to {beta}-but not -cells in islets and it is independent of MT-binding. Knockdown of CAMSAP2 by shRNA impairs Golgi-ER trafficking, reduces total insulin content, and attenuates GSIS without affecting the MT dynamics or releasability of insulin granules in islet {beta}-cells. Corresponding to these results, we found that primary islets and MIN6 cells express different CAMSAP2 isoforms. We propose that primary islet {beta} cells use a novel CAMSAP2 isoform for a MT-independent non-canonical function, which is to promote Golgi-ER trafficking that supports efficient production of insulin secretory granules.

cell biology↗

bioRxiv2020

Microtubules regulate pancreatic beta cell heterogeneity via spatiotemporal control of insulin secretion hot spots

Heterogeneity of glucose-stimulated insulin secretion (GSIS) in pancreatic islets is physiologically important but poorly understood. Here, we utilize whole mouse islets to determine how microtubules affect secretion toward the vascular extracellular matrix. Our data indicate that microtubule stability in the {beta}-cell population is heterogenous, and that cells with more stable microtubules secrete less in response to a stimulus. Consistently, microtubule hyper-stabilization prevents, and microtubule depolymerization promotes {beta}-cell activation. Analysis of spatiotemporal patterns of secretion events shows that microtubule depolymerization activates otherwise dormant {beta}-cells via initiation of secretion clusters (hot spots). Microtubule depolymerization also enhances secretion from individual cells, introducing both additional clusters and scattered events. Interestingly, without microtubules, the timing of clustered secretion is dysregulated, extending the first phase of GSIS. Our findings uncover a novel microtubule function in tuning insulin secretion hot spots, which leads to accurately measured and timed response to glucose stimuli and promotes functional {beta}-cell heterogeneity.

cell biology↗