Excitable RhoA dynamics drive pulsed contractions in the early C. elegans embryo

Pulsed actomyosin contractility underlies diverse modes of tissue morphogenesis, but the underlying mechanisms remain poorly understood. Here, we combined quantitative imaging with genetic perturbations to identify a core mechanism for pulsed contractility in early Caenorhabditis elegans embryos. We show that pulsed accumulation of actomyosin is governed by local control of assembly and disassembly downstream of RhoA. Pulsed activation and inactivation of RhoA precede, respectively, the accumulation and disappearance of actomyosin and persist in the absence of Myosin II. We find that fast (likely indirect) autoactivation of RhoA drives pulse initiation, while delayed, F-actin–dependent accumulation of the RhoA GTPase-activating proteins RGA-3/4 provides negative feedback to terminate each pulse. A mathematical model, constrained by our data, suggests that this combination of feedbacks is tuned to generate locally excitable RhoA dynamics. We propose that excitable RhoA dynamics are a common driver for pulsed contractility that can be tuned or coupled differently to actomyosin dynamics to produce a diversity of morphogenetic outcomes.

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Excitable RhoA dynamics drive pulsed contractions in the early C. elegans embryo

10.1101/076356 ◽

2016 ◽

Cited By ~ 3

Author(s):

Jonathan B. Michaux ◽

François B. Robin ◽

William M. McFadden ◽

Edwin M. Munro

Keyword(s):

Mathematical Model ◽

Quantitative Imaging ◽

Myosin Ii ◽

C Elegans ◽

Rhoa Activation ◽

Gtpase Activating Proteins ◽

Actomyosin Contractility ◽

Rhoa Gtpase ◽

Genetic Perturbations ◽

Underlying Mechanisms

AbstractPulsed actomyosin contractility underlies diverse modes of tissue morphogenesis, but the underlying mechanisms remain poorly understood. Here, we combine quantitative imaging with genetic perturbations to identify a core mechanism for pulsed contractility in early C. elegans embryos. We show that pulsed accumulation of actomyosin is governed by local control of assembly and disassembly downstream of RhoA. Pulsed activation and inactivation of RhoA precede, respectively, accumulation and disappearance of actomyosin, and persist in the nearly complete absence of Myosin II. We find that fast positive feedback on RhoA activation drives pulse initiation, while F-actin dependent accumulation of the RhoA GTPase activating proteins (GAPs) RGA-3/4 provides delayed negative feedback to terminate each pulse. An experimentally constrained mathematical model confirms that in principle these feedbacks are sufficient to generate locally excitable RhoA dynamics. We propose that excitable RhoA dynamics are a common driver for pulsed contractility that can be differently tuned or coupled to actomyosin dynamics to produce a diversity of morphogenetic outcomes.

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LMO7-dependent apical constriction requires the binding of the Myosin heavy chain

10.1101/2021.05.12.443820 ◽

2021 ◽

Author(s):

Miho Matsuda ◽

Chih-Wen Chu ◽

Sergei S Sokol

Keyword(s):

Heavy Chain ◽

Myosin Light Chain ◽

Myosin Ii ◽

Tube Formation ◽

Epithelial Morphogenesis ◽

Apical Constriction ◽

Actomyosin Contractility ◽

Apical Domain ◽

Underlying Mechanisms ◽

Muscle Myosin

The reduction of the apical domain, or apical constriction, is a process that occurs in a single cell or is coordinated in a group of cells in the epithelium. Coordinated apical constriction is particularly important when the epithelium is undergoing dynamic morphogenetic events such as furrow or tube formation. However, the underlying mechanisms remain incompletely understood. Here we show that Lim only protein 7 (Lmo7) is a novel activator of apical constriction in the Xenopus superficial ectoderm, which coordinates actomyosin contractility in a group of cells during epithelial morphogenesis. Like other apical constriction regulators, Lmo7 requires the activation of the Rho-Rock-Myosin II pathway to induce apical constriction. However, instead of increasing the phosphorylation of myosin light chain (MLC), Lmo7 binds muscle myosin II heavy chain A (NMIIA) and increases its association with actomyosin bundles at adherens junctions (AJs). Lmo7 overexpression modulates the subcellular distribution of Wtip, a tension marker at AJs, suggesting that Lmo7 generates mechanical forces at AJs. We propose that Lmo7 increases actomyosin contractility at AJs by promoting the formation of actomyosin bundles.

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Faculty Opinions recommendation of Wnt/Frizzled signaling controls C. elegans gastrulation by activating actomyosin contractility.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1046818.496855 ◽

2006 ◽

Author(s):

Morris Maduro

Keyword(s):

C Elegans ◽

Actomyosin Contractility

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Myosinome: A Database of Myosins from Select Eukaryotic Genomes to Facilitate Analysis of Sequence-Structure-Function Relationships

Bioinformatics and Biology Insights ◽

10.4137/bbi.s9902 ◽

2012 ◽

Vol 6 ◽

pp. BBI.S9902 ◽

Cited By ~ 3

Author(s):

Divya P. Syamaladevi ◽

Margaret S Sunitha ◽

S. Kalaimathy ◽

Chandrashekar C. Reddy ◽

Mohammed Iftekhar ◽

...

Keyword(s):

Conformational Changes ◽

Atp Hydrolysis ◽

Homo Sapiens ◽

Relevant Literature ◽

Myosin Ii ◽

Coiled Coil ◽

Structural Features ◽

Model Organisms ◽

Congenital Diseases ◽

C Elegans

Myosins are one of the largest protein superfamilies with 24 classes. They have conserved structural features and catalytic domains yet show huge variation at different domains resulting in a variety of functions. Myosins are molecules driving various kinds of cellular processes and motility until the level of organisms. These are ATPases that utilize the chemical energy released by ATP hydrolysis to bring about conformational changes leading to a motor function. Myosins are important as they are involved in almost all cellular activities ranging from cell division to transcriptional regulation. They are crucial due to their involvement in many congenital diseases symptomatized by muscular malfunctions, cardiac diseases, deafness, neural and immunological dysfunction, and so on, many of which lead to death at an early age. We present Myosinome, a database of selected myosin classes (myosin II, V, and VI) from five model organisms. This knowledge base provides the sequences, phylogenetic clustering, domain architectures of myosins and molecular models, structural analyses, and relevant literature of their coiled-coil domains. In the current version of Myosinome, information about 71 myosin sequences belonging to three myosin classes (myosin II, V, and VI) in five model organisms ( Homo Sapiens, Mus musculus, D. melanogaster, C. elegans and S. cereviseae) identified using bioinformatics surveys are presented, and several of them are yet to be functionally characterized. As these proteins are involved in congenital diseases, such a database would be useful in short-listing candidates for gene therapy and drug development. The database can be accessed from http://caps.ncbs.res.in/myosinome .

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The Molecular Basis and Therapeutic Potential of Let-7 MicroRNAs against Colorectal Cancer

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2018/5769591 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 16

Author(s):

Rei Mizuno ◽

Kenji Kawada ◽

Yoshiharu Sakai

Keyword(s):

Colorectal Cancer ◽

Molecular Basis ◽

Posttranscriptional Regulation ◽

Therapeutic Agent ◽

Therapeutic Potential ◽

Noncoding Rnas ◽

Intestinal Tumorigenesis ◽

C Elegans ◽

Microrna Family ◽

Underlying Mechanisms

Although a number of studies have revealed the underlying mechanisms which regulate the development of colorectal cancer (CRC), we have not completely overcome this disease yet. Accumulating evidence has shown that the posttranscriptional regulation by the noncoding RNAs such as microRNAs plays an important role in the development or progression of CRC. Among a number of microRNAs, the let-7 microRNA family that was first discovered in C. elegans and conserved from worms to humans has been linked with the development of many types of cancers including CRC. The expression level of let-7 microRNAs is temporally low during the normal developmental processes, while elevated in the differentiated tissues. The let-7 microRNAs regulate the cell proliferation, cell cycle, apoptosis, metabolism, and stemness. In CRC, expressions of let-7 microRNAs have been reported to be reduced, and so let-7 microRNAs are considered to be a tumor suppressor. In this review, we discuss the mechanisms regulating the let-7 microRNA expression and the downstream targets of let-7 in the context of intestinal tumorigenesis. The application of let-7 mimics is also highlighted as a novel therapeutic agent.

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Multiple neural bHLHs ensure the precision of a neuronal specification event in C. elegans

Biology Open ◽

10.1242/bio.058976 ◽

2021 ◽

Author(s):

Konstantina Filippopoulou ◽

Carole Couillault ◽

Vincent Bertrand

Keyword(s):

Transcription Factors ◽

Quantitative Imaging ◽

Terminal Differentiation ◽

Cholinergic Neurons ◽

Antagonistic Effect ◽

Specific Class ◽

C Elegans ◽

Neuronal Specification ◽

Bhlh Transcription Factors ◽

Deleterious Genes

Neural bHLH transcription factors play a key role in the early steps of neuronal specification in many animals. We have previously observed that the Achaete-Scute HLH-3, the Olig HLH-16 and their binding partner the E protein HLH-2 activate the terminal differentiation program of a specific class of cholinergic neurons, AIY, in C. elegans. Here we identify a role for a fourth bHLH, the Neurogenin NGN-1, in this process, raising the question of why so many neural bHLHs are required for a single neuronal specification event. Using quantitative imaging we show that the combined action of different bHLHs is needed to activate the correct level of expression of the terminal selector transcription factors TTX-3 and CEH-10 that subsequently initiate and maintain the expression of a large battery of terminal differentiation genes. Surprisingly, the different bHLHs have an antagonistic effect on another target, the proapoptotic BH3-only factor EGL-1, normally not expressed in AIY and otherwise detrimental for its specification. We propose that the use of multiple neural bHLHs allows robust neuronal specification while, at the same time, preventing spurious activation of deleterious genes.

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TRPV channel OCR-2 is distributed along C. elegans chemosensory cilia by diffusion in a local interplay with intraflagellar transport

10.1101/2020.11.19.390005 ◽

2020 ◽

Author(s):

Jaap van Krugten ◽

Noémie Danné ◽

Erwin J.G. Peterman

Keyword(s):

Single Molecule ◽

Transmembrane Proteins ◽

Intraflagellar Transport ◽

Single Molecule Tracking ◽

C Elegans ◽

Normal Diffusion ◽

Cellular Signal ◽

Underlying Mechanisms ◽

And Function

AbstractSensing and reacting to the environment is essential for survival and procreation of most organisms. Caenorhabditis elegans senses soluble chemicals with transmembrane proteins (TPs) in the cilia of its chemosensory neurons. Development, maintenance and function of these cilia relies on intraflagellar transport (IFT), in which motor proteins transport cargo, including sensory TPs, back and forth along the ciliary axoneme. Here we use live fluorescence imaging to show that IFT machinery and the sensory TP OCR-2 reversibly redistribute along the cilium after exposure to repellant chemicals. To elucidate the underlying mechanisms, we performed single-molecule tracking experiments and found that OCR-2 distribution depends on an intricate interplay between IFT-driven transport, normal diffusion and subdiffusion that depends on the specific location in the cilium. These insights in the role of IFT on the dynamics of cellular signal transduction contribute to a deeper understanding of the regulation of sensory TPs and chemosensing.

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WDR31 is a novel ciliopathy protein displaying functional redundancy with GTPase-activating proteins ELMOD and RP2 in recruiting BBSome to cilium

10.21203/rs.3.rs-622797/v1 ◽

2021 ◽

Author(s):

Sebiha Cevik ◽

Lama Alabdi ◽

Xiaoyu Peng ◽

Tina Beyer ◽

Atiyye Zorluer ◽

...

Keyword(s):

Clinical Features ◽

Renal Agenesis ◽

Rare Disorders ◽

Compartment Analysis ◽

C Elegans ◽

Gtpase Activating Proteins ◽

Mechanistic Analysis ◽

Evolutionarily Conserved ◽

Null Mutants

Abstract The term “ciliopathy” refers to a group of over 35 rare disorders characterized by defective cilia and many overlapping clinical features, such as hydrocephalus, cerebellar vermis hypoplasia, polydactyly, and retinopathy. Even though many genes have been implicated in ciliopathies, the genetic pathogenesis in certain cases remains still undisclosed. Here, we identified a homozygous truncating variant in WDR31 in a patient with a typical ciliopathy phenotype encompassing congenital hydrocephalus, polydactyly, and renal agenesis. WDR31 is an evolutionarily conserved protein that localizes to the cilium and cilia-related compartment. Analysis from zebrafish supports the role of WDR31 in regulating the cilia morphology. The CRISPR/Cas9 knock-in (p.Arg261del) C. elegans model of the patient variant (p.Arg268*) reproduced several cilia-related defects observed in wdr-31 null mutants. Mechanistic analysis from C. elegans revealed that WDR-31 functions redundantly with ELDM-1 (ELMOD protein) and RPI-2 (RP2) to regulate the IFT trafficking through controlling the cilia entry of the BBSome. This work revealed WDR31 as a new ciliopathy protein that regulates IFT and BBSome trafficking.

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Polar relaxation by dynein-mediated removal of cortical myosin II

The Journal of Cell Biology ◽

10.1083/jcb.201903080 ◽

2020 ◽

Vol 219 (8) ◽

Cited By ~ 4

Author(s):

Bernardo Chapa-y-Lazo ◽

Motonari Hamanaka ◽

Alexander Wray ◽

Mohan K. Balasubramanian ◽

Masanori Mishima

Keyword(s):

Recent Work ◽

Molecular Mechanism ◽

Molecular Mechanisms ◽

Myosin Ii ◽

Cell Cortex ◽

Cleavage Furrow ◽

Contractile Ring ◽

C Elegans ◽

Polar Cell

Nearly six decades ago, Lewis Wolpert proposed the relaxation of the polar cell cortex by the radial arrays of astral microtubules as a mechanism for cleavage furrow induction. While this mechanism has remained controversial, recent work has provided evidence for polar relaxation by astral microtubules, although its molecular mechanisms remain elusive. Here, using C. elegans embryos, we show that polar relaxation is achieved through dynein-mediated removal of myosin II from the polar cortexes. Mutants that position centrosomes closer to the polar cortex accelerated furrow induction, whereas suppression of dynein activity delayed furrowing. We show that dynein-mediated removal of myosin II from the polar cortexes triggers a bidirectional cortical flow toward the cell equator, which induces the assembly of the actomyosin contractile ring. These results provide a molecular mechanism for the aster-dependent polar relaxation, which works in parallel with equatorial stimulation to promote robust cytokinesis.

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