bioRxiv Science⌕ Search

Biology subjects

Oegema, K.

Publications and source records attributed to Oegema, K..

At least 19 recordsLinked to original sources

A tissue-targeted auxin-inducible degradation toolkit for C. elegans embryogenesis

Many proteins required for embryogenesis are expressed in multiple tissues and across developmental time, often with tissue- and stage-specific roles. To resolve where and when proteins function, we developed a tissue-targeted auxin-inducible degradation toolkit for C. elegans embryogenesis. We generated a plasmid set compatible with single-copy insertion or high-copy extrachromosomal array generation that employs tissue-specific promoters (active in the germline, intestine, muscle, pharynx, neuroblasts, neurons, sensory neurons, epidermis, and pan soma) to drive an operon expressing an optimized auxin-dependent plant F-box factor TIR1 and, in most cases, a fluorescent histone. Using a ubiquitous nuclear envelope marker as a test substrate, we identified single-copy insertions and arrays that exhibit efficient auxin-dependent, tissue-specific target degradation. We also establish a workflow that ensures all functionally important isoforms of a target are tagged and that degradation reproduces the loss-of-function phenotype prior to tissue-specific analysis. Applying the toolkit to the broadly expressed Rho kinase LET-502, we find that degradation in the epidermis, but not in other embryonic tissues, disrupts elongation. Unexpectedly, temporal analysis revealed that LET-502 is required for late as well as early elongation.

developmental biology↗

TMEM209/NPP-28 partitions PLK-1 between the nuclear envelope and nuclear interior during mitosis

The onset of mitosis in animal cells is marked by nuclear envelope breakdown (NEBD), which requires coordinated disassembly of nuclear pore complexes (NPCs) and the nuclear lamina. Polo-like kinase 1 (Plk1/PLK-1) initiates NEBD through phosphorylation of NPC components, but mechanisms that spatially regulate PLK-1 between NPCs and the nuclear interior are unclear. Here, we identify the Caenorhabditis elegans TMEM209 homolog NPP-28 as a transmembrane nucleoporin that concentrates PLK-1 at the nuclear envelope while limiting its nuclear accumulation to promote NEBD. We identify docking sites within NPP-28 that mediate PLK-1 nuclear envelope-association. NPP-28 is phosphorylated by PLK-1 in vitro, and mutational analysis suggests that NPP-28-mediated docking facilitates NEBD, whereas phosphorylation prevents premature NEBD. Simultaneous loss of npp-28 and the transmembrane nucleoporin npp-12/gp210 exacerbates mitotic NEBD defects in early embryos and causes severe defects in germline development. Together, our findings identify NPP-28 as a spatial regulator of PLK-1 during mitosis with functional relationships with other conserved transmembrane nucleoporins depending on context.

cell biology↗

Inhibitor-2 directs formation of PP1 holoenzymes through a docking motif-dependent transfer of catalytic subunits to adapters

The catalytic subunits of protein phosphatase 1 (PP1) achieve spatiotemporal substrate specificity by assembling with diverse regulatory adapters to form holoenzymes. Three conserved proteins--Sds22, Inhibitor-2 and Inhibitor-3--facilitate loading of PP1 catalytic subunits (PP1cs) onto adapters. We show here that Inhibitor-2 is central to a dynamic cycle that directs formation of adapter-bound PP1 holoenzymes. Inhibitor-2 engages PP1cs via two adapter-like docking motifs (RVxF and SILK) and an active site-binding inhibitory region. While Inhibitor-2 depletion produced moderate phenotypes, mutation of its RVxF docking motif caused severe defects resembling global PP1c inhibition. The RVxF mutant did not prevent PP1c binding or reduce PP1c stability but inhibited formation of adapter-bound holoenzymes. The severe effects of the RVxF mutation were suppressed by linked mutation of the inhibitory active site-binding motif. These results suggest that Inhibitor-2 is integral to a dynamic cycle that delivers PP1cs to adapters, with its RVxF motif being critical for coupling relief of active site inhibition to adapter handoff.

cell biology↗

The mitotic stopwatch synergizes with mild p53 activation to halt cell proliferation

The mitotic stopwatch suppresses proliferation of cell lineages experiencing prolonged mitosis that are prone to chromosome missegregation and tumorigenesis. It converts extended mitotic duration into heritable USP28-53BP1 complexes that stabilize p53 and accumulate over generations. To identify genes whose knockout activates the stopwatch, we performed a CRISPR/Cas9 screen comparing dropout kinetics of essential-gene gRNAs in cells lacking versus possessing the stopwatch. Two classes of knockouts emerged: one (27/60 top hits) that prolonged mitosis, and another (33/60 top hits) that mildly elevated p53 without significant mitotic defects, indicating that the stopwatch synergizes with mild p53 activation to halt proliferation. Mild p53 elevation lowered the stopwatch complex threshold for daughter cell arrest and slightly prolonged mitosis. Integrated over successive divisions, the cumulative effect of multiple short mitotic extensions triggered stopwatch-dependent arrest. Thus, the mitotic stopwatch endows the p53 network with a durable lineage memory of modest stress, explaining its tumor-suppressive role.

cell biology↗

Phosphorylation remodels the mitotic centrosome matrix to generate bipartite gamma-tubulin complex docking sites

Mitotic centrosomes consist of centrioles surrounded by a proteinaceous matrix that docks and activates {gamma}-tubulin complexes ({gamma}TuCs) to nucleate microtubules for spindle assembly. During mitotic entry, phosphorylation at centrosomes remodels CDK5RAP2 family matrix proteins to generate {gamma}TuC docking sites. We address the mechanism of this conversion using C. elegans SPD-5 as a model. We show that SPD-5 contains two regions, PRGB1 and PRGB2, that are each sufficient for Polo-Like Kinase 1 (PLK1) phosphorylation-regulated {gamma}TuC binding. We define key phosphosites in each region and uncover autoinhibition mediated by interactions within and between them. PRGB2 is dimeric and requires {gamma}TuCs containing the Mozart family microprotein MZT-1 for binding, whereas PRGB1 is monomeric and binds independently of MZT-1. Our results support PLK1 phosphorylation inducing a conformational change that enables MZT-1-dependent PRGB2 binding, which in turn relieves PRGB1 inhibition. Such a multi-step mechanism would ensure robust spindle assembly by restricting microtubule nucleation in space and time.

cell biology↗

A chromatin-associated pool of Aurora A controls kinetochore-microtubule attachments to ensure chromosome biorientation

Accurate chromosome segregation requires dynamic kinetochore-microtubule attachments that, under the regulation of Aurora family kinases, biorient and align replicated chromosomes. In C. elegans, Aurora A acts with the TPX2-related activator TPXL-1 to regulate these attachments and control spindle length. We show that, in addition to prominent spindle pole localization, TPXL-1-AurA has a chromatin-associated pool positioned between the sister kinetochores. Structural modeling and biochemical analysis support TPXL-1 directly recognizing the nucleosome acidic patch via an arginine anchor. Disrupting this interaction selectively removed chromatin-bound TPXL-1-AurA and caused chromosome missegregation, whereas elevation of the chromatin pool disrupted chromosome alignment. These opposing perturbations inversely affected kinetochore recruitment of the microtubule-binding Ska complex. These results support spatially distinct TPXL-1-AurA populations acting sequentially, with the spindle pole pool controlling spindle length by switching kinetochores out of a depolymerization-coupled state, and the chromatin pool controlling attachment stabilization to ensure biorientation prior to anaphase.

cell biology↗

The CYK-4 GAP domain regulates cortical targeting of centralspindlin to promote contractile ring assembly and facilitate ring dissolution

During cytokinesis, an equatorial contractile ring partitions the cell contents. Contractile ring assembly requires an equatorial zone of active GTP-bound RhoA generated by the guanine nucleotide exchange factor ECT21,2. ECT2 is activated by centralspindlin, a complex composed of two molecules each of kinesin-6 and CYK4. During anaphase, Centralspindlin is activated at the central spindle between the separating chromosomes and diffuses to the plasma membrane, where it engages with ECT2 via its N-terminal half3,4. The C-terminal half of CYK4 contains a lipid-binding C1 domain that contributes to plasma membrane targeting5 and a GTPase-activating protein (GAP) domain that has an interaction surface for a Rho family GTPase, whose functions have remained unclear 1,3,4,6,7. Here, using the one-cell stage C. elegans embryo as a model, we show that RhoA and the Rho-binding interface of the CYK4 GAP domain drive the recruitment of centralspindlin to the equatorial cortex. By contrast, a point mutant that selectively disrupts GAP activity does not prevent cortical centralspindlin recruitment but instead substantially delays dissipation of centralspindlin from the cortex. These findings suggest that positive feedback, in which centralspindlin recruitment promotes the generation of active RhoA and active RhoA drives centralspindlin recruitment, is central to the rapid assembly of the contractile ring within a narrow time window. They also indicate that the CYK4 GAP catalytic activity contributes to release of centralspindlin from the cortex, potentially to ensure timely dissolution of the contractile ring.

cell biology↗

Hybrid incompatibility emerges at the one-cell stage in interspecies Caenorhabditis embryos

Intrinsic reproductive isolation occurs when genetic divergence between populations disrupts hybrid development, preventing gene flow and enforcing speciation.1-4 Over the past two decades, researchers have identified molecular mechanisms underlying a few dozen cases of hybrid incompatibility in animals.5 Much of this work has focused on mismatches in zygotic gene regulation,6-11 but other mechanisms have also emerged, including symbiont-driven incompatibilities,12 nucleoporin mismatches affecting nuclear-cytoplasmic transport,13 and divergence in centromeric or heterochromatic regions and their regulatory proteins which can lead to the inability of the oocyte cytoplasm to segregate sperm-derived chromosomes.14-19 Since studies to date have focused on a limited number of species, uncovering mechanisms across diverse taxa will be important to understanding broader patterns of hybrid incompatibility. Here, we investigate the mechanistic basis of hybrid incompatibility in Caenorhabditis nematodes by leveraging the ability of C. brenneri females to produce embryos after mating with males from several other species. We find that incompatibilities emerge between fertilization and the onset of zygotic transcription, which begins at the 4-cell stage.20-23 In Caenorhabditis embryos, as in many animals,24,25 sperm deliver chromatin and centrioles into the oocyte.26-29 After remaining quiescent during oocyte meiosis, the sperm chromatin acquires a nuclear envelope, and centrioles initiate centrosome formation.30-32 Centrosomes remain tethered to the sperm pronucleus, which positions them near the cortex to establish anterior-posterior polarity.33,34 We identify two key processes that are destabilized in hybrids: (1) the ability of oocytes to control sperm-derived pronuclear expansion, and (2) successful polar body formation. When sperm pronuclear expansion is delayed, centrosomes detach, which leads to defects in polarity establishment. Hybrid embryos typically experience one or more stochastic failures of early developmental events that accumulate and eventually kill them.

evolutionary biology↗

TRIM37 employs peptide motif recognition and substrate-dependent oligomerization to prevent ectopic spindle pole assembly

Tightly controlled duplication of centrosomes, the major microtubule-organizing centers of animal cells, ensures bipolarity of the mitotic spindle and accurate chromosome segregation. The RBCC (RING-B-box-coiled coil) ubiquitin ligase TRIM37, whose loss is associated with elevated chromosome missegregation and the tumor-prone developmental human disorder Mulibrey nanism, prevents the formation of ectopic spindle poles that assemble around structured condensates containing the centrosomal protein centrobin. Here, we show that TRIM37s TRAF domain, unique in the extended TRIM family, engages peptide motifs in centrobin to suppress condensate formation. TRIM proteins form anti-parallel coiled-coil dimers with RING-B-box domains on each end. Oligomerization due to RING-RING interactions and conformational regulation by B-box-2-B-box-2 interfaces are critical for TRIM37 to suppress centrobin condensate formation. These results indicate that, analogous to anti-viral TRIM ligases, TRIM37 activation is linked to the detection of oligomerized substrates. Thus, TRIM37 couples peptide motif recognition and substrate-dependent oligomerization to effect ubiquitination-mediated clearance of ectopic centrosomal protein assemblies.

cell biology↗

Phospho-KNL-1 recognition by a TPR domain targets the BUB-1/BUB-3 complex to C. elegans kinetochores

During mitosis, the Bub1-Bub3 complex concentrates at kinetochores, the microtubule-coupling interfaces on chromosomes, where it contributes to spindle checkpoint activation, kinetochore-spindle microtubule interactions, and protection of centromeric cohesion. Bub1 has a conserved N-terminal tetratricopeptide (TPR) domain followed by a binding motif for its conserved interactor Bub3. The current model for Bub1-Bub3 localization to kinetochores is that Bub3, along with its bound motif from Bub1, recognizes phosphorylated "MELT" motifs in the kinetochore scaffold protein Knl1. Motivated by the greater phenotypic severity of BUB-1 versus BUB-3 loss in C. elegans, we show that the BUB-1 TPR domain directly recognizes a distinct class of phosphorylated motifs in KNL-1 and that this interaction is essential for BUB-1-BUB-3 localization and function. BUB-3 recognition of phospho-MELT motifs additively contributes to drive super-stoichiometric accumulation of BUB-1-BUB-3 on its KNL-1 scaffold during mitotic entry. Bub1s TPR domain interacts with Knl1 in other species, suggesting that collaboration of TPR-dependent and Bub3-dependent interfaces in Bub1-Bub3 localization and functions may be conserved.

cell biology↗

Cyclin B3 is a dominant fast-acting cyclin that drives rapid early embryonic mitoses

In many species, early embryonic mitoses proceed at a very rapid pace, but how this pace is achieved is not understood. Here we show that in the early C. elegans embryo, cyclin B3 is the dominant driver of rapid embryonic mitoses. Metazoans typically have three cyclin B isoforms that associate with and activate Cdk1 kinase to orchestrate mitotic events: the related cyclins B1 and B2 and the more divergent cyclin B3. We show that whereas embryos expressing cyclins B1 and B2 support slow mitosis (NEBD to Anaphase [~] 600s), the presence of cyclin B3 dominantly drives the [~]3-fold faster mitosis observed in wildtype embryos. CYB-1/2-driven mitosis is longer than CYB-3-driven mitosis primarily because the progression of mitotic events itself is slower, rather than delayed anaphase onset due to activation of the spindle checkpoint or inhibitory phosphorylation of the anaphase activator CDC-20. Addition of cyclin B1 to cyclin B3-only mitosis introduces an [~]60s delay between the completion of chromosome alignment and anaphase onset, which likely ensures segregation fidelity; this delay is mediated by inhibitory phosphorylation on CDC-20. Thus, the dominance of cyclin B3 in driving mitotic events, coupled to introduction of a short cyclin B1-dependent delay in anaphase onset, sets the rapid pace and ensures fidelity of mitoses in the early C. elegans embryo.

cell biology↗

Control of cell proliferation by memories of mitosis

Mitotic duration is tightly constrained, with extended mitotic duration being a characteristic of potentially problematic cells prone to chromosome missegregation and genomic instability. We show that memories of mitotic duration are integrated by a p53-based mitotic stopwatch pathway to exert tight control over proliferation. The stopwatch halts proliferation of the products of a single significantly extended mitosis or of successive modestly extended mitoses. Time in mitosis is monitored via mitotic kinase-regulated assembly of stopwatch complexes that are transmitted to daughter cells. The stopwatch is inactivated in p53-mutant cancers, as well as in a significant proportion of p53-wildtype cancers, consistent with classification of stopwatch complex subunits as tumor suppressors. Stopwatch status additionally influences efficacy of anti-mitotic agents currently used or in development for cancer therapy. One-Sentence SummaryTime spent in mitosis is carefully monitored to halt the proliferation of potentially dangerous cells in a population.

cancer biology↗

PLK-1 tethered on BUB-1 directs CDC-20 kinetochore recruitment to ensure timelyembryonic mitoses

During mitosis chromosomes assemble kinetochores in order to dynamically couple with spindle microtubules (Cheeseman, 2014; Musacchio & Desai, 2017). Kinetochores also function as signaling hubs directing mitotic progression by recruiting and controlling the fate of the Anaphase Promoting Complex/Cyclosome (APC/C) activator CDC-20 (Lara-Gonzalez et al., 2017; Lara-Gonzalez, Pines, et al., 2021; Musacchio, 2015). Kinetochores either incorporate CDC-20 into checkpoint complexes that inhibit the APC/C or dephosphorylate CDC-20, which allows it to interact with and activate the APC/C (Kim et al., 2017; Lara-Gonzalez et al., 2017). The importance of these two CDC-20 fates likely depends on biological context. In somatic cells the major mechanism controlling mitotic progression is the spindle checkpoint. By contrast, progression through mitosis during the cell cycles of early embryos is largely checkpoint-independent (Clute & Masui, 1995; Duro & Nilsson, 2021; Gerhart et al., 1984; Zhang et al., 2015). Here, by manipulating CDC-20 phosphorylation status, we show that CDC-20 phosphoregulation controls mitotic duration in the C. elegans embryo and defines a checkpoint-independent temporal mitotic optimum for robust embryogenesis. Flux of CDC-20 through kinetochores for local dephosphorylation requires an ABBA motif on BUB-1 that directly interfaces with the structured WD40 domain of CDC-20 (Di Fiore et al., 2015; Diaz-Martinez et al., 2015; He et al., 2013; Kim et al., 2017). We show that a conserved "STP" motif in BUB-1 that docks the mitotic kinase PLK-1 (Qi et al., 2006) is also necessary to recruit CDC-20 to kinetochores and for timely mitotic progression. The kinase activity of PLK-1 is required for CDC-20 to localize to kinetochores and targets a site within the CDC-20-binding ABBA motif of BUB-1; phosphorylation of this site promotes BUB-1-CDC-20 interaction and mitotic progression. Thus, the BUB-1-bound pool of PLK-1 ensures timely mitosis during embryonic cell cycles by promoting CDC-20 recruitment to the vicinity of kinetochore-localized phosphatase activity.

cell biology↗

The N-terminal Tail of C. elegans CENP-A Interacts with KNL-2 and is Essential for Centromeric Chromatin Assembly

Centromeres are epigenetically defined by the presence of the centromere-specific histone H3 variant CENP-A. A specialized loading machinery, including the histone chaperone HJURP/Scm3, participates in CENP-A nucleosome assembly. However, Scm3/HJURP is missing from multiple lineages, including nematodes, which rely on a CENP-A-dependent centromere. Here, we show that the extended N-terminal tail of C. elegans CENP-A contains a predicted structured region that is essential for centromeric chromatin assembly. Removal of this region of the CENP-A N-Tail prevents loading, resulting in failure of kinetochore assembly and defective chromosome condensation. By contrast, the N-Tail mutant CENP-A localizes normally in the presence of endogenous CENP-A. The portion of the N-Tail containing the predicted structured region binds to KNL-2, a conserved SANTA and Myb domain-containing protein (referred to as M18BP1 in vertebrates), that is specifically involved in CENP-A chromatin assembly. This direct interaction is conserved in the related nematode C. briggsae, despite divergence of the N-Tail and KNL-2 primary sequences. Thus, the extended N-Tail of CENP-A is essential for CENP-A chromatin assembly in C. elegans and partially substitutes for the function of Scm3/HJURP, in that it mediates an interaction of the specialized histone fold of CENP-A with KNL-2. These results highlight an evolutionary variation on centromeric chromatin assembly in the absence of a dedicated CENP-A-specific chaperone/targeting factor of the Scm3/HJURP family.

cell biology↗

Polo-like kinase 1 independently controls microtubule-nucleating capacity and size of the centrosome

Centrosomes are composed of a centriolar core surrounded by a pericentriolar material (PCM) matrix that docks microtubule-nucleating {gamma}-tubulin complexes. During mitotic entry, the PCM matrix increases in size and nucleating capacity in a process called centrosome maturation. Polo-like kinase 1 (PLK1) localizes to centrosomes and phosphorylates PCM matrix proteins to drive their self-assembly, which leads to PCM expansion; this expansion has been assumed to passively increase microtubule nucleation to support spindle assembly. Here, we show that PLK1 directly controls the generation of binding sites for {gamma}-tubulin complexes on the PCM matrix, independently of PCM expansion. Selective inhibition of PLK1-dependent {gamma}-tubulin docking leads to spindle defects and impaired chromosome segregation, without affecting PCM expansion, highlighting the importance of phospho-regulated centrosomal {gamma}-tubulin docking sites in spindle assembly. Inhibiting both {gamma}-tubulin docking and PCM expansion by mutating substrate target sites fully accounts for the actions of PLK-1 in transforming the centrosome during mitotic entry. Summary StatementPolo-like kinase 1-mediated physical expansion of centrosomes during mitotic entry is proposed to passively increase their microtubule nucleating capacity. Ohta et al. show instead that generation of microtubule-nucleating sites is directly controlled by Polo-like kinase 1, independently of centrosome size.

cell biology↗

Ancestral Roles of the Fam20C Family of Secreted Protein Kinases Revealed by Functional Analysis in C. elegans

Fam20C is a secreted protein kinase mutated in Raine syndrome, a human skeletal disorder. In vertebrates, bone and enamel proteins are major Fam20C substrates. However, Fam20 kinases are conserved in invertebrates lacking bone and enamel, suggesting other ancestral functions. We show that FAMK-1, the C. elegans Fam20C ortholog, contributes to fertility, embryogenesis, and development. These functions are not fulfilled when FAMK-1 is retained in the early secretory pathway. During embryogenesis, FAMK-1 maintains inter-cellular partitions and prevents multinucleation; notably, temperature elevation or lowering cortical stiffness reduces requirement for FAMK-1 in this context. FAMK-1 is expressed in multiple adult tissues that undergo repeated mechanical strain, and selective expression in the spermatheca restores fertility. Informatic, biochemical and functional analysis implicate lectins as FAMK-1 substrates. These findings suggest that FAMK-1 phosphorylation of substrates, including lectins, in the late secretory pathway is important in embryonic and tissue contexts where cells are subjected to mechanical strain.

cell biology↗

TPXL-1 Activates Aurora A to Clear Contractile Ring Components from the Polar Cortex During Cytokinesis

During cytokinesis, a signal from the bundled microtubules that form between the separating anaphase chromosomes promotes the accumulation of contractile ring components at the cell equator, while a signal from the centrosomal microtubule asters inhibits accumulation of contractile ring components at the cell poles. However, the molecular identity of the inhibitory signal has remained unknown. To identify molecular components of the aster-based inhibitory signal, we developed a means to monitor the removal of contractile ring proteins from the polar cortex after anaphase onset. Using this assay, we show that polar clearing is an active process that requires activation of Aurora A kinase by TPXL-1. TPXL-1 concentrates on astral microtubules coincident with polar clearing in anaphase, and its ability to recruit Aurora A and activate its kinase activity are essential for clearing. In summary, our data identify Aurora A kinase as an aster-based inhibitory signal that restricts contractile ring components to the cell equator during cytokinesis.\n\nSUMMARYDuring cytokinesis, centrosomal asters inhibit cortical contractility at the cell poles. Mangal et al. provide molecular insight into this phenomenon, showing that TPXL-1, which localizes to astral microtubules, activates Aurora A kinase to clear contractile ring proteins from the polar cortex.

cell biology↗

CYK-4 functions independently of its centralspindlin partner ZEN-4 to cellularize oocytes in germline syncytia

Throughout metazoans, germ cells undergo incomplete cytokinesis to form syncytia connected by intercellular bridges. Formation of gametes ultimately requires bridge closure. Here, we investigate the contribution of the conserved bridge component centralspindlin to oocyte production in C. elegans. Centralspindlin is composed of the Rho family GTPase-activating protein (GAP) CYK-4/MgcRacGAP and the microtubule motor ZEN-4/kinesin-6, which are both essential for cytokinesis. In contrast, we show that oocyte production by the syncytial germline requires CYK-4 but not ZEN-4. Longitudinal imaging after conditional CYK-4 inactivation revealed a role in oocyte cellularization, rather than in generation of syncytial compartments. CYK-4s lipid-binding C1 domain and the GTPase-binding interface of its GAP domain were individually important for oocyte cellularization and for targeting CYK-4 to bridges, where it contributes to enrichment of active RhoA. These results identify a C1-GAP module in CYK-4 that recruits it to bridges in the germline and directs their closure to produce oocytes.\n\nIMPACT STATEMENTThe CYK-4 subunit of centralspindlin, a broadly conserved component of intercellular bridges across metazoa, is required for the cytokinesis-like closure of intercellular bridges that cellularizes oocytes to separate them from germline syncytia.\n\nMAJOR SUBJECT AREASCell Biology, Developmental Biology & Stem Cells

cell biology↗