Biology subjects

Conradt, B.

Publications and source records attributed to Conradt, B..

4 recordsLinked to original sources

bioRxiv2024

Non-random segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in daughter cells

The non-random segregation of organelles has been proposed to be an intrinsic mechanism that contributes to cell fate divergence during asymmetric cell division; however, in vivo evidence is sparse. Using super-resolution microscopy, we analysed the segregation of organelles during the division of the neuroblast QL.p in C. elegans larvae. QL.p divides to generate a daughter that survives, QL.pa, and a daughter that dies, QL.pp. We found that mitochondria segregate unequally by density and morphology and that this is dependent on mitochondrial fission and fusion. Furthermore, we found that mitochondrial density in QL.pp correlates with the time it takes QL.pp to die. We propose that low mitochondrial density in QL.pp promotes the cell death fate and ensures that QL.pp dies in a highly reproducible and timely manner. Our results provide the first in vivo evidence that the non-random segregation of mitochondria can contribute to cell fate divergence during asymmetric cell division.

developmental biology↗

bioRxiv2024

The replicative helicase CMG is required for the divergence of cell fates during asymmetric cell division in vivo

The mechanisms that enable differential gene expression in daughter cells produced by asymmetric cell divisions are not well understood. We discovered that the eukaryotic replicative helicase CMG (Cdc45-MCM-GINS) is required for this process in C. elegans. During C. elegans development, some dividing cells give rise to a daughter that survives and a daughter that dies. We found that PSF-2 GINS2, a component of C. elegans CMG, is necessary for the transcriptional burst of the pro-apoptotic gene egl-1 BH3-only, which occurs in the daughter that dies immediately following mother cell division. We present evidence that this requirement is independent of the function of CMG in DNA unwinding. We propose that the recently described histone chaperone activity of CMG causes epigenetic changes at the egl-1 locus during replication in mother cells, and that these changes are required for the increase in egl-1 transcription in the daughter that dies. We also find that PSF-2 is required for the divergence of other cell fates during C. elegans development, suggesting that this function is not restricted to the regulation of egl-1 expression. Our work uncovers a new and unexpected role of CMG in cell fate and a novel intrinsic mechanism for gene expression plasticity in the context of asymmetric cell division.

cell biology↗

bioRxiv2020

Genome-wide RNAi screen for regulators of UPRmt in Caenorhabditis elegans mutants with defects in mitochondrial fusion

The disruption of mitochondrial dynamics has detrimental consequences for mitochondrial and cellular homeostasis and leads to the activation of the mitochondrial unfolded protein response (UPRmt), a quality control mechanism that adjusts cellular metabolism and restores homeostasis. To identify genes involved in the induction of UPRmt in response to a block in mitochondrial fusion, we performed a genome-wide RNAi screen in Caenorhabditis elegans mutants lacking the gene fzo-1, which encodes the ortholog of mammalian Mitofusin. We find that approximately 90% of the 299 suppressors and 86 enhancers identified are conserved in humans and that one third of the conserved genes have been implicated in human disease. Furthermore, many of the 385 genes have roles in developmental processes, which suggests that mitochondrial function and the response to stress are defined during development and maintained throughout life. In addition, we find that enhancers are predominantly mitochondrial genes and suppressors non-mitochondrial genes, which indicates that the maintenance of mitochondrial homeostasis has evolved as a critical cellular function that when disrupted can be compensated for by a variety of cellular processes. Our analysis of non-mitochondrial enhancers and mitochondrial suppressors suggests that organellar contact sites, especially between ER and mitochondria, are of importance for mitochondrial homeostasis. Finally, we uncovered several genes involved in IP3 signaling that modulate UPRmt in fzo-1 mutants, found a potential link between pre-mRNA splicing and UPRmt activation and identified the Miga-1/2 ortholog K01D12.6 as required for mitochondrial dynamics in C. elegans.

cell biology↗

bioRxiv2020

PIG-1 MELK-dependent phosphorylation of nonmuscle myosin II promotes apoptosis through CES-1 Snail partitioning

The mechanism(s) through which mammalian kinase MELK promotes tumorigenesis is not understood. We find that the C. elegans orthologue of MELK, PIG-1, promotes apoptosis by partitioning an anti-apoptotic factor. The C. elegans NSM neuroblast divides to produce a larger cell that differentiates into a neuron and a smaller cell that dies. We find that in this context, PIG-1 is required for partitioning of CES-1 Snail, a transcriptional repressor of the pro-apoptotic gene egl-1 BH3-only. pig-1 MELK is controlled by both a ces-1 Snail- and par-4 LKB1-dependent pathway, and may act through phosphorylation and cortical enrichment of nonmuscle myosin II prior to neuroblast division. We propose that pig-1 MELK-induced local contractility of the actomyosin network plays a conserved role in the acquisition of the apoptotic fate. Our work also uncovers an auto-regulatory loop through which ces-1 Snail controls its own activity through the formation of a gradient of CES-1 Snail protein. Significance StatementApoptosis is critical for the elimination of unwanted cells. What distinguishes wanted from unwanted cells in developing animals is poorly understood. We report that in the C. elegans NSM neuroblast lineage, the level of CES-1, a Snail-family member and transcriptional repressor of the pro-apoptotic gene egl-1, contributes to this process. In addition, we demonstrate that C. elegans PIG-1, the orthologue of mammalian proto-oncoprotein MELK, plays a critical role in controlling CES-1Snail levels. Specifically, during NSM neuroblast division, PIG-1MELK controls partitioning of CES-1Snail into one but not the other daughter cell thereby promoting the making of one wanted and one unwanted cell. Furthermore, we present evidence that PIG-1MELK acts prior to NSM neuroblast division by locally activating the actomyosin network.

developmental biology↗