Biology subjects

Jetten, A. M.

Publications and source records attributed to Jetten, A. M..

5 recordsLinked to original sources

bioRxiv2026

GLIS3 is a key regulator of astrocyte differentiation in human neural stem cells

Astrocytes play a key role in neuronal homeostasis and in various neural disorders. The generation of astrocytes from neural progenitor cells (NPCs) and its functions are under a complex control of several signaling networks and transcription factors. In this study, we demonstrate that the transcription factor, GLIS similar 3 (GLIS3), which has been implicated in several neurodegenerative diseases, is highly expressed in astrocytes, and is required for the efficient differentiation of human NPCs into astrocytes. Loss of GLIS3 function greatly impairs astrocytes differentiation, resulting in reduced expression of astrocyte markers, whereas expression of exogenous GLIS3 restores the induction of astrocyte specific genes indicating a critical role for GLIS3 in astrocyte differentiation. Integrated transcriptomic and cistromic analyses revealed that GLIS3 directly regulates the transcription of several astrocyte-associated genes, including GFAP, SLC1A2, NFIA, and ATF3, in coordination with lineage-determining factors, such as STAT3, NFIA, and SOX9. We hypothesize that GLIS3 dysfunction disrupts this transcriptional network thereby contributing to astrocyte-associated neurological disorders. Identification of GLIS3 as a key regulator of astrocyte differentiation and gene expression will advance our understanding of its role in neurodegenerative diseases and may provide a new therapeutic target.

developmental biology↗

bioRxiv2026

Identification of distinct functions of GLIS3 in β-cell generation critical to prevention of neonatal diabetes

GLIS3 plays a critical role in pancreatic {beta} cells and diabetes, being one of only a few genes implicated in Type 1, Type 2, and Gestational diabetes. In addition to {beta} cells, GLIS3 is expressed embryonically in bipotent and proendocrine progenitor cells, suggesting a role in endocrine lineage development in mice. We hypothesize that GLIS3 is playing important roles in endocrine development as well as during {beta} cell differentiation. We utilized single cell RNA-sequencing at three different timepoints (embryonic day (e)13.5, e15.5, and e18.5) and single nucleus (sn)ATAC-sequencing at e15.5 in both wild type (WT) and Glis3 Knockout (Glis3KO) mouse embryos. This analysis revealed that the numbers of bipotent, proendocrine progenitor, and all subsequent endocrine cells were proportionately reduced in Glis3KO mice. Additionally, loss of GLIS3 function generates a unique subpopulation of cells that fail to upregulate Ins2 transcription and downregulate expression of several ribosomal and oxidative phosphorylation genes normally repressed during pre{beta} to {beta} cell differentiation. Our study therefore shows that GLIS3 regulates two distinct stages: the embryonic generation/differentiation of bipotent cells and the differentiation of pre{beta} to {beta} cells. Dysregulation of these two stages provides a causal mechanism for the development of neonatal diabetes in GLIS3-deficiency.

developmental biology↗

bioRxiv2024

Circadian regulation of CaV1.2 expression by RORalpha in the mouse heart

BackgroundIn addition to show autonomous beating rhythmicity, the physiological functions of the heart present daily periodic oscillations. Notably the ventricular repolarization itself varies throughout the circadian cycle which was mainly related to the periodic expression of K+ channels. However, the involvement of the L-type Ca2+ channel (CaV1.2 encoded by Cacna1c gene) in these circadian variations remains elusive. MethodsWe used a transgenic mouse model (PCa-luc) that expresses the luciferase reporter under the control of the cardiac Cacna1c promoter and analyzed promoter activity by bioluminescent imaging, qPCR, immunoblot, Chromatin immunoprecipitation assay (ChIP) and CaV1.2 activity. ResultsUnder normal 12:12h light-dark cycle, we observed in vivo a biphasic diurnal variation of promoter activities peaking at 9 and 19.5 Zeitgeber time (ZT). This was associated with a periodicity of Cacna1c mRNA levels preceding 24-h oscillations of CaV1.2 protein levels in ventricle (with a 1.5 h phase shift) but not in atrial heart tissues. The periodicity of promoter activities and CaV1.2 proteins, which correlated with biphasic oscillations of L-type Ca2+ current conductance, persisted in isolated ventricular cardiomyocytes from PCa-Luc mice over the course of the 24-h cycle, suggesting an endogenous cardiac circadian regulation. Comparison of 24-h temporal patterns of clock gene expressions in ventricles and atrial tissues of the same mice revealed conserved circadian oscillations of the core clock genes except for the retinoid-related orphan receptor gene (ROR), which remained constant throughout the course of a day in atrial tissues. In vitro we found that ROR is recruited to two specific regions on the Cacna1c promoter and that incubation with specific ROR inhibitor disrupted 24-h oscillations of ventricular promoter activities and CaV1.2 protein levels. Similar results were observed for pore forming subunits of the K+ transient outward currents, KV4.2 and KV4.3. ConclusionsThese findings raise the possibility that the ROR-dependent rhythmic regulation of cardiac CaV1.2 and KV4.2/4.3 throughout the daily cycle may play an important role in physiopathology of heart function.

physiology↗

bioRxiv2021

GLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans

Chronically elevated intraocular pressure (IOP) is the major risk factor of primary open- angle glaucoma, a leading cause of blindness. Dysfunction of the trabecular meshwork (TM), which controls the outflow of aqueous humor (AqH) from the anterior chamber, is the major cause of elevated IOP. Here, we demonstrate that mice deficient in the Kruppel- like zinc finger transcriptional factor GLI-similar-1 (GLIS1) develop chronically elevated IOP. Magnetic resonance imaging and histopathological analysis reveal that deficiency in GLIS1 expression induces progressive degeneration of the TM, leading to inefficient AqH drainage from the anterior chamber and elevated IOP. Transcriptome and cistrome analyses identified several glaucoma- and extracellular matrix-associated genes as direct transcriptional targets of GLIS1. We also identified a significant association between GLIS1 variant rs941125 and glaucoma in humans (P=4.73x10-6), further supporting a role for GLIS1 into glaucoma etiology. Our study identifies GLIS1 as a critical regulator of TM function and maintenance, AqH dynamics, and IOP.

molecular biology↗

bioRxiv2020

The nuclear receptor RORα preserves cardiomyocyte mitochondrial function by regulating mitophagy through caveolin-3

Preserving optimal mitochondrial function is critical in the heart, which is the most ATP-avid organ in the body. Recently, we showed that global deficiency of the nuclear receptor ROR in the "staggerer" (RORsg/sg) mouse exacerbates angiotensin II-induced cardiac hypertrophy and compromises cardiomyocyte mitochondrial function. The mechanisms underlying these observations have not been defined. Here we present evidence that ROR regulates cardiomyocyte mitophagy using pharmacological and genetic gain- and loss-of-function tools, including a novel cardiomyocyte-specific ROR knockout mouse. Cardiomyocyte ROR is upregulated by hypoxia and the loss of ROR blunts hypoxia-induced mitophagy and broadly compromises mitochondrial function. We show that ROR is a direct transcriptional regulator of the mitophagy mediator caveolin-3 in cardiomyocytes and that increased expression of ROR increases caveolin-3 abundance and enhances mitophagy. Knockdown of ROR impairs cardiomyocyte mitophagy, but this defect can be rescued by caveolin-3 overexpression. Collectively, these findings reveal a novel role for ROR in regulating mitophagy through caveolin-3 and expand our currently limited understanding of the mechanisms underlying ROR-mediated cardioprotection.

molecular biology↗