Biology subjects

Gotz, M.

Publications and source records attributed to Gotz, M..

3 recordsLinked to original sources

bioRxiv2026

Cilia beating of ependymal cells regulates adult neural stem cell quiescence via mechanical forces mediated by PKD1/2-TRPM3

In many tissues stem cells are located lining a fluid-filled volume and their neighboring niche cells include cells with beating cilia. However, the role of mechanical forces created by cilia beating on stem cells remains elusive. We developed an approach to transiently inhibit the cilia beating of ependymal cells (EC) lining the forebrain ventricle by injecting magnetic beads-coupled antibodies targeting EC cilia and then applying a magnetic field. We show that EC cilia beating enforces neural stem cells (NSCs) quiescence through mechano-sensitive PKD1/2- and TRPM3-mediated Ca2+ transients. Only a few hours of EC cilia beating inhibition triggered NSC activation in vivo. CRISPR-Cas9-mediated deletion of TRPM3 or PKD1/2 in NSCs phenocopied the effect of EC cilia beating inhibition, while TRPM3 pharmacological activation rescued NSC quiescence in the absence of cilia beating. Our data reveal a novel regulator of stem cells exposed to fluids via the mechanical forces mediated by cilia beating.

neuroscience↗

bioRxiv2025

Suppression rather than activation of the integrated-stress-response (GCN2-ATF4) pathway extends lifespan in the fly

Stress response pathways are emerging as conserved modulators of lifespan. The prevailing hypothesis is that activation of stress responsive pathways, including the amino acid deprivation arm of the integrated stress response (ISR; the GCN2-ATF4 pathway) is pro-longevity. Activation of ATF4 orthologs extends lifespan in Saccharomyces cerevisiae (yeast) and Caenorhabditis elegans, but its role in other longer-lived organisms remains unclear. We comprehensively tested the role of the GCN2-ATF4 pathway in the fly (Drosophila melanogaster) for the first time. We used conditional genetic manipulation of dGCN2 and its downstream effector Drosophila ATF4 (crc; dATF4). In contrast to previous studies, we show that overexpression of dGCN2 and dATF4 significantly reduces lifespan, while knockdown (in vivo RNAi) of dATF4 extends lifespan. We confirmed dATF4 activity was successfully modulated using a fluorescent dATF4 activation reporter. Borrelidin, a tRNA synthetase inhibitor, significantly reduced lifespan in a both dATF4 and diet-dependent manner, independent of microbial load, showing our modulation of dATF4 altered nutrient to ISR signalling. We further conducted long-read RNA sequencing and found that our manipulation of dATF4 changed global transcription in opposite directions, including known ATF4 target genes. Enrichment analysis revealed that dATF4 overexpression may drive metabolic stress, while dATF4 knockdown upregulates proteostasis and DNA repair pathways. Our work reveals that ATF4 exhibits a dual, dose- and context-dependent role in ageing. Chronic dATF4 activation is detrimental in flies, while chronic suppression is pro-longevity. The GCN2-ATF4 pathway thus qualifies as a modifiable control of lifespan with cross-species relevance.

physiology↗

bioRxiv2017

Cooperative nucleotide binding in Hsp90 and the underlying mechanisms

The function of the molecular chaperone Hsp90 depends on large conformational changes, rearrangement of local motifs, as well as the binding and hydrolysis of ATP. The complexity of the Hsp90 system impedes the detailed investigation of their interplay using standard methods. By the application of three-color single molecule FRET to Hsp90 and a reporter nucleotide, we directly observe cooperativity between the two nucleotide binding pockets in the protein dimer. Through allocating the microscopic states and extracting their kinetics, we identify the mechanisms underlying the cooperativity. Surprisingly, nucleotide binding affects several state transitions, which demonstrates the complexity of cooperativity in protein systems. The co-chaperone Aha1, known to accelerate Hsp90's ATPase activity, adds another layer of complexity by affecting transitions in a nucleotide-dependent and -independent manner.

biophysics↗