Biology subjects

Gueler, B. E.

Publications and source records attributed to Gueler, B. E..

3 recordsLinked to original sources

bioRxiv2025

KCNQ1 regulates human neuronal development through mitochondrial and insulin signalling pathways

KCNQ1 encodes a voltage-gated potassium channel implicated in various peripheral and neurological disorders, yet its role during human neuronal development remains unclear. To investigate this, we generated KCNQ1 knockouts (KO) in human induced pluripotent stem cell lines and differentiated them into neural stem cells (NSCs) and cortical neurons. KCNQ1-deficient NSCs showed impaired neurite outgrowth, linked to reduced cell adhesion and disrupted neural cell adhesion molecule (NCAM) signalling. This phenotype was reproduced in wild-type and heterozygous lines by pharmacological KCNQ1 inhibition. Whole transcriptome, proteome, and follow-up analyses revealed mitochondrial dysfunction in KO NSCs, including reduced mitochondrial copy number and ATP synthase expression. Additionally, evidence was obtained for an impairment of insulin signalling in NSCs and neurons, with diminished insulin receptor gene expression and perturbation of key downstream signalling pathways (RAS-MAPK, PI3K-AKT). In neurons, KCNQ1 loss resulted in decreased synaptic activity and a more immature gene expression profile. Overall, our work reveals a novel role for KCNQ1 in human neurodevelopment by regulating cell adhesion, mitochondrial function, and insulin signalling. This work increases our understanding of KCNQ1 function in neurons and its contribution to neurological phenotypes observed in patients with KCNQ1-related diseases.

molecular biology↗

bioRxiv2024

The BBS/CCT chaperonin complex ensures the localization of the adhesion G protein-coupled receptor ADGRV1 to primary cilia

Primary cilia are antenna-like sensory organelles present on almost all eukaryotic cells. Their sensory capacity relies on receptors, in particular G-protein-coupled receptors (GPCRs) which localize to the ciliary membrane. Here we show that ADGRV1, a member of the GPCR subfamily of adhesion GPCRs, is part of a large protein network, interacting with numerous proteins of a comprehensive ciliary proteome. ADGRV1 is localized to the base of prototypic primary cilia in cultured cells and the modified primary cilia of retinal photoreceptors, where it interacts with TRiC/CCT chaperonins and the Bardet Biedl syndrome (BBS) chaperonin-like proteins. Knockdown of ADGRV1, CCT2 and 3, and BBS6 result in common ciliogenesis phenotypes, namely reduced ciliated cells combined with shorter primary cilia. In addition, the localization of ADGRV1 to primary cilia depends on the activity of a co-complex of TRiC/CCT chaperonins and the BBS chaperonin-like proteins. In the absence of components of the TRiC/CCT-BBS chaperonin co-complex, ADGRV1 is depleted from the base of the primary cilium and degraded via the proteasome. Defects in the TRiC/CCT-BBS chaperonin may lead to an overload of proteasomal degradation processes and imbalanced proteostasis. Dysfunction or absence of ADGRV1 from primary cilia may underly the pathophysiology of human Usher syndrome type 2 and epilepsy caused by mutations in ADGRV1.

cell biology↗

bioRxiv2024

The adhesion GPCR ADGRV1 controls glutamate homeostasis in hippocampal astrocytes supporting neuron development: First insights into to pathophysiology of ADGRV1-associated epilepsy

ADGRV1 is the largest member of adhesion G protein-coupled receptor (aGPCR) family. In the cell, aGPCRs have dual roles in cell adhesion and signal transduction. Mutations in ADGRV1 have been linked not only to Usher syndrome (USH), which causes deaf-blindness, but recently also to various forms of epilepsy. While the USH defects are attributed to the loss of fiber links between membranes formed by the extracellular domain of ADGRV1, the pathomechanisms leading to epilepsy remain elusive to date. Here, we study the specific functions of ADGRV1 in astrocytes where it is highest expressed in the nervous system. Affinity proteomics showed the interaction of ADRGV1 with proteins enriched in astrocytes. Dysregulations of cellular processes important in astrocyte function were indicated by the different transcriptomes of patient-derived cells and Adgrv1-deficent mouse hippocampi compared to appropriate controls. Alteration in morphology and reduced numbers of astrocytes in the hippocampus of Adgrv1-deficent mice. Monitoring the glutamate uptake in colorimetric assay and by live cell imaging of a genetic glutamate reporter consistently showed that glutamate uptake from the extracellular environment is significantly reduced in Adgrv1-deficent astrocytes. Expression analyses of key enzymes of the glutamate-glutamine cycle in astrocytes and the glutamate metabolism indicated imbalanced glutamate homeostasis in Adgrv1-deficient astrocytes. Finally, we provide evidence that the supportive function of astrocytes in neuronal development also relies on ADGRV1 expression in astrocytes. Our data collectively provides first insights into the molecular pathophysiology underlying the development of epilepsy associated with mutations in ADGRV1. HighlightsO_LIADGRV1 deficiency reduces the number of astrocytes in CA1 and changes the morphology of astrocytes in the hippocampus. C_LIO_LIADGRV1 interacts with numerous proteins enriched in astrocytes. C_LIO_LIDifferential transcriptomes revealed differential expression of genes related to glutamate homeostasis and epilepsy in ADGRV1 deficient models. C_LIO_LIADGRV1 controls glutamate uptake and regulates homeostasis in astrocytes. C_LIO_LIADGRV1 in astrocytes is vital for neuron morphogenesis. C_LIO_LIFirst insights into the molecular pathophysiology underlying the development of epilepsy associated with mutations in ADGRV1. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=197 SRC="FIGDIR/small/591120v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1f1f749org.highwire.dtl.DTLVardef@a1ea01org.highwire.dtl.DTLVardef@a0be1org.highwire.dtl.DTLVardef@191f96a_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗