scholarly journals Forkhead transcription factor FKH-8 is a master regulator of primary cilia in C. elegans

2021 ◽  
Author(s):  
Rebeca Brocal-Ruiz ◽  
Ainara Esteve-Serrano ◽  
Carlos Mora-Martinez ◽  
Peter Swoboda ◽  
Juan Tena ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Genetic Diseases ◽  
Ciliated Cell ◽  
Cell Types ◽  
Forkhead Transcription Factor ◽  
Master Regulator ◽  
C Elegans ◽  
Direct Activation ◽  
Wide Range ◽  
Motile Cilia

SUMMARYCilia, either motile or non-motile (a.k.a primary or sensory), are complex evolutionary conserved eukaryotic structures composed of hundreds of proteins required for their assembly, structure and function that are collectively known as the ciliome. Ciliome mutations underlie a group of pleiotropic genetic diseases known as ciliopathies. Proper cilium function requires the tight coregulation of ciliome gene transcription, which is only fragmentarily understood. RFX transcription factors (TF) have an evolutionarily conserved role in the direct activation of ciliome genes both in motile and non-motile cilia cell types. In vertebrates, FoxJ1 and FoxN4 Forkhead (FKH) TFs work with RFX in the direct activation of ciliome genes, exclusively in motile cilia cell-types. No additional TFs have been described to act together with RFX in primary cilia cell-types in any organism. Here we describe FKH-8, a FKH TF, as master regulator of the primary ciliome in Caenorhabditis elegans. fkh-8 is expressed in all ciliated neurons in C. elegans, binds the regulatory regions of ciliome genes, regulates ciliome gene expression, cilium morphology and a wide range of behaviours mediated by sensory cilia. Importantly, we find FKH-8 function can be replaced by mouse FOXJ1 and FOXN4 but not by members of other mouse FKH subfamilies. In conclusion, our results show that RFX and FKH TF families act as master regulators of ciliogenesis also in sensory ciliated cell types and suggest that this regulatory logic could be an ancient trait predating functional cilia sub-specialization.

scholarly journals Primary Cilia and Calcium Signaling Interactions

2020 ◽  
Vol 21 (19) ◽  
pp. 7109
Author(s):  
Hannah Saternos ◽  
Sidney Ley ◽  
Wissam AbouAlaiwi
Keyword(s):  
Primary Cilia ◽  
Cell Types ◽  
Cellular Level ◽  
Cellular Functions ◽  
Complex Processes ◽  
Secondary Messenger ◽  
Body Patterning ◽  
Motile Cilia ◽  
And Migration ◽  
Context Specific

The calcium ion (Ca2+) is a diverse secondary messenger with a near-ubiquitous role in a vast array of cellular processes. Cilia are present on nearly every cell type in either a motile or non-motile form; motile cilia generate fluid flow needed for a variety of biological processes, such as left–right body patterning during development, while non-motile cilia serve as the signaling powerhouses of the cell, with vital singling receptors localized to their ciliary membranes. Much of the research currently available on Ca2+-dependent cellular actions and primary cilia are tissue-specific processes. However, basic stimuli-sensing pathways, such as mechanosensation, chemosensation, and electrical sensation (electrosensation), are complex processes entangled in many intersecting pathways; an overview of proposed functions involving cilia and Ca2+ interplay will be briefly summarized here. Next, we will focus on summarizing the evidence for their interactions in basic cellular activities, including the cell cycle, cell polarity and migration, neuronal pattering, glucose-mediated insulin secretion, biliary regulation, and bone formation. Literature investigating the role of cilia and Ca2+-dependent processes at a single-cellular level appears to be scarce, though overlapping signaling pathways imply that cilia and Ca2+ interact with each other on this level in widespread and varied ways on a perpetual basis. Vastly different cellular functions across many different cell types depend on context-specific Ca2+ and cilia interactions to trigger the correct physiological responses, and abnormalities in these interactions, whether at the tissue or the single-cell level, can result in diseases known as ciliopathies; due to their clinical relevance, pathological alterations of cilia function and Ca2+ signaling will also be briefly touched upon throughout this review.

scholarly journals xbx-4, a homolog of the Joubert syndrome gene FAM149B1, acts via the CCRK and MAK kinase cascade to regulate cilia morphology

2021 ◽  
Author(s):  
Ashish K Maurya ◽  
Piali Sengupta
Keyword(s):  
Sensory Neuron ◽  
Mammalian Cells ◽  
Primary Cilia ◽  
Cell Types ◽  
Joubert Syndrome ◽  
C Elegans ◽  
Kinase Cascade ◽  
Multiple Cell ◽  
Kinase Pathway ◽  
Sensory Functions

Primary cilia are microtubule (MT)-based organelles that mediate sensory functions in multiple cell types. Disruption of cilia structure or function leads to a diverse collection of diseases termed ciliopathies. Mutations in the DUF3719 domain-containing protein FAM149B1 have recently been shown to elongate cilia via unknown mechanisms and result in the ciliopathy Joubert syndrome. The highly conserved CCRK and MAK/RCK kinases negatively regulate cilia length and structure in Chlamydomonas, C. elegans, and mammalian cells. How the activity of this kinase cascade is tuned to precisely regulate cilia architecture is unclear. Here we identify XBX-4, a DUF3719 domain-containing protein related to human FAM149B1, as a novel regulator of the DYF-18 CCRK and DYF-5 MAK kinase pathway in C. elegans. As in dyf-18 and dyf-5 mutants, sensory neuron cilia are elongated in xbx-4 mutants and exhibit altered axonemal MT stability. XBX-4 promotes DYF-18 CCRK activity to regulate DYF-5 MAK function and localization. We find that Joubert syndrome-associated mutations in the XBX-4 DUF3719 domain also elongate cilia in C. elegans. Our results identify a new metazoan-specific regulator of this highly conserved kinase pathway, and suggest that FAM149B1 may similarly act via the CCRK/MAK kinase pathway to regulate ciliary homeostasis in humans.

scholarly journals The Roles of Primary Cilia in Cardiovascular Diseases

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 233 ◽  
Author(s):  
Rajasekharreddy Pala ◽  
Maha Jamal ◽  
Qamar Alshammari ◽  
Surya Nauli
Keyword(s):  
Cardiovascular Diseases ◽  
Primary Cilia ◽  
Cell Types ◽  
Molecular Defects ◽  
Flow Sensing ◽  
Intracellular Signals ◽  
Wide Range ◽  
No Signaling ◽  
Vascular Endothelia ◽  
And Function

Primary cilia are microtubule-based organelles found in most mammalian cell types. Cilia act as sensory organelles that transmit extracellular clues into intracellular signals for molecular and cellular responses. Biochemical and molecular defects in primary cilia are associated with a wide range of diseases, termed ciliopathies, with phenotypes ranging from polycystic kidney disease, liver disorders, mental retardation, and obesity to cardiovascular diseases. Primary cilia in vascular endothelia protrude into the lumen of blood vessels and function as molecular switches for calcium (Ca2+) and nitric oxide (NO) signaling. As mechanosensory organelles, endothelial cilia are involved in blood flow sensing. Dysfunction in endothelial cilia contributes to aberrant fluid-sensing and thus results in vascular disorders, including hypertension, aneurysm, and atherosclerosis. This review focuses on the most recent findings on the roles of endothelial primary cilia within vascular biology and alludes to the possibility of primary cilium as a therapeutic target for cardiovascular disorders.

scholarly journals Ocular Ciliopathies: Genetic and Mechanistic Insights into Developing Therapies

2019 ◽  
Vol 26 (17) ◽  
pp. 3120-3131 ◽  
Author(s):  
Mahesh Shivanna ◽  
Manisha Anand ◽  
Subhabrata Chakrabarti ◽  
Hemant Khanna
Keyword(s):  
Outer Segment ◽  
Genetic Diseases ◽  
Ciliated Cell ◽  
Anterior Segment ◽  
Treatment Strategies ◽  
Cell Types ◽  
Aqueous Fluid ◽  
Disease Manifestation ◽  
Genetic Components ◽  
Suitable Treatment

Developing suitable medicines for genetic diseases requires a detailed understanding of not only the pathways that cause the disease, but also the identification of the genetic components involved in disease manifestation. This article focuses on the complexities associated with ocular ciliopathies – a class of debilitating disorders of the eye caused by ciliary dysfunction. Ciliated cell types have been identified in both the anterior and posterior segments of the eye. Photoreceptors (rods and cones) are the most studied ciliated neurons in the retina, which is located in the posterior eye. The photoreceptors contain a specialized lightsensing outer segment, or cilium. Any defects in the development or maintenance of the outer segment can result in severe retinal ciliopathies, such as retinitis pigmentosa and Leber congenital amaurosis. A role of cilia in the cell types involved in regulating aqueous fluid outflow in the anterior segment of the eye has also been recognized. Defects in these cell types are frequently associated with some forms of glaucoma. Here, we will discuss the significance of understanding the genetic heterogeneity and the pathogenesis of ocular ciliopathies to develop suitable treatment strategies for these blinding disorders.

scholarly journals Lineage-specific control of convergent differentiation by a Forkhead repressor

2019 ◽  
Author(s):  
Karolina Mizeracka ◽  
Julia M. Rogers ◽  
Jonathan D. Rumley ◽  
Shai Shaham ◽  
Martha L. Bulyk ◽  
...  
Keyword(s):  
Cell Types ◽  
Human Homolog ◽  
Cell Type ◽  
Forkhead Transcription Factor ◽  
C Elegans ◽  
Identical Cell ◽  
Cell Type Specific ◽  
Activate Cell ◽  
Type Specification ◽  
Specific Control

ABSTRACTDuring convergent differentiation, multiple developmental lineages produce a highly similar or identical cell type. However, the molecular players that drive convergent differentiation are not known. Here, we show that the C. elegans Forkhead transcription factor UNC-130 is required in only one of three convergent lineages that produce the same glial cell type. UNC-130 acts transiently as a repressor in progenitors and newly-born terminal cells to allow the proper specification of cells related by lineage rather than by cell type. Specification defects correlate with UNC-130:DNA binding, and UNC-130 can be functionally replaced by its human homolog, the neural crest lineage determinant FoxD3. We propose that, in contrast to terminal selectors that activate cell-type specific transcriptional programs in terminally differentiating cells, UNC-130 acts earlier to enable molecularly distinct progenitors to produce equivalent cell types. These findings provide evidence that convergent differentiation involves distinct transcriptional paths leading to the same cell type.

scholarly journals Myosin concentration underlies cell size–dependent scalability of actomyosin ring constriction

2011 ◽  
Vol 195 (5) ◽  
pp. 799-813 ◽  
Author(s):  
Meredith E.K. Calvert ◽  
Graham D. Wright ◽  
Fong Yew Leong ◽  
Keng-Hwee Chiam ◽  
Yinxiao Chen ◽  
...  
Keyword(s):  
Filamentous Fungus ◽  
Mechanical Characteristics ◽  
Cell Types ◽  
Contractile Ring ◽  
C Elegans ◽  
Size Dependent ◽  
Wide Range ◽  
Similar Mode ◽  
Ring Constriction ◽  
Myosin Motors

In eukaryotes, cytokinesis is accomplished by an actomyosin-based contractile ring. Although in Caenorhabditis elegans embryos larger cells divide at a faster rate than smaller cells, it remains unknown whether a similar mode of scalability operates in other cells. We investigated cytokinesis in the filamentous fungus Neurospora crassa, which exhibits a wide range of hyphal circumferences. We found that N. crassa cells divide using an actomyosin ring and larger rings constricted faster than smaller rings. However, unlike in C. elegans, the total amount of myosin remained constant throughout constriction, and there was a size-dependent increase in the starting concentration of myosin in the ring. We predict that the increased number of ring-associated myosin motors in larger rings leads to the increased constriction rate. Accordingly, reduction or inhibition of ring-associated myosin slows down the rate of constriction. Because the mechanical characteristics of contractile rings are conserved, we predict that these findings will be relevant to actomyosin ring constriction in other cell types.

scholarly journals PACRG, a protein linked to ciliary motility, mediates cellular signaling

2016 ◽  
Vol 27 (13) ◽  
pp. 2133-2144 ◽  
Author(s):  
Catrina M. Loucks ◽  
Nathan J. Bialas ◽  
Martijn P. J. Dekkers ◽  
Denise S. Walker ◽  
Laura J. Grundy ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Cellular Signaling ◽  
Cell Types ◽  
Small Subset ◽  
Protein Signaling ◽  
Sensory Physiology ◽  
Ciliary Motility ◽  
C Elegans ◽  
Sensory Signaling ◽  
Associated Proteins

Cilia are microtubule-based organelles that project from nearly all mammalian cell types. Motile cilia generate fluid flow, whereas nonmotile (primary) cilia are required for sensory physiology and modulate various signal transduction pathways. Here we investigate the nonmotile ciliary signaling roles of parkin coregulated gene (PACRG), a protein linked to ciliary motility. PACRG is associated with the protofilament ribbon, a structure believed to dictate the regular arrangement of motility-associated ciliary components. Roles for protofilament ribbon–associated proteins in nonmotile cilia and cellular signaling have not been investigated. We show that PACRG localizes to a small subset of nonmotile cilia in Caenorhabditis elegans, suggesting an evolutionary adaptation for mediating specific sensory/signaling functions. We find that it influences a learning behavior known as gustatory plasticity, in which it is functionally coupled to heterotrimeric G-protein signaling. We also demonstrate that PACRG promotes longevity in C. elegans by acting upstream of the lifespan-promoting FOXO transcription factor DAF-16 and likely upstream of insulin/IGF signaling. Our findings establish previously unrecognized sensory/signaling functions for PACRG and point to a role for this protein in promoting longevity. Furthermore, our work suggests additional ciliary motility-signaling connections, since EFHC1 (EF-hand containing 1), a potential PACRG interaction partner similarly associated with the protofilament ribbon and ciliary motility, also positively regulates lifespan.

scholarly journals Matrix stiffness controls ciliogenesis and centriole position

2021 ◽  
Author(s):  
Ivanna Williantarra ◽  
Sophia Leung ◽  
Yu Suk Choi ◽  
Ashika Chhana ◽  
Susan R McGlashan
Keyword(s):  
Primary Cilium ◽  
Cellular Response ◽  
Primary Cilia ◽  
Basal Membrane ◽  
Cell Types ◽  
Substrate Stiffness ◽  
Dependent Manner ◽  
Wide Range ◽  
The Matrix ◽  
External Forces

Mechanical stress and the stiffness of the extracellular matrix are key drivers of tissue development and homeostasis. Aberrant mechanosensation is associated with a wide range of pathologies, including diseases such as osteoarthritis. Substrate stiffness is one of the well-known mechanical properties of the matrix that enabled establishing the central dogma of an integrin-mediated mechanotransduction using stem cells. However, how specific cells 'feel' or sense substrate stiffness requires further study. The primary cilium is an essential cellular organelle that senses and integrates mechanical and chemical signals from the extracellular environment. We hypothesised that the primary cilium dynamically alters its length and position to fine-tune cell mechanosignalling based on substrate stiffness alone. We used a hydrogel system of varying substrate stiffness to examine the role of substrate stiffness on cilia frequency, length and centriole position as well as cell and nuclei area over time. Contrary to other cell types, we show that chondrocyte primary cilia shorten on softer substrates demonstrating tissue-specific mechanosensing which is aligned with the tissue stiffness the cells originate from. We further show that stiffness alone determine centriole positioning to either the basal or apical membranes during attachment and spreading, with centriole positioned towards the basal membrane on stiffer substrates. These phenomena are mediated by force generation actin-myosin stress fibres in a time-dependent manner. Based on these findings, we propose that substrate stiffness plays a central role in cilia positioning, regulating cellular response to external forces, and may be a key driver of mechanosignalling-associated diseases.

scholarly journals Distinct gating mechanism of SOC channel involving STIM–Orai coupling and an intramolecular interaction of Orai in Caenorhabditis elegans

2018 ◽  
Vol 115 (20) ◽  
pp. E4623-E4632 ◽  
Author(s):  
Kyu Min Kim ◽  
Tharaka Wijerathne ◽  
Jin-Hoe Hur ◽  
Uk Jung Kang ◽  
Ihn Hyeong Kim ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Intramolecular Interaction ◽  
Interaction Mechanism ◽  
Cell Types ◽  
C Elegans ◽  
Gating Mechanism ◽  
Wide Range ◽  
Store Operated Calcium Entry ◽  
Cellular Compartments ◽  
Orai Channels

Store-operated calcium entry (SOCE), an important mechanism of Ca2+ signaling in a wide range of cell types, is mediated by stromal interaction molecule (STIM), which senses the depletion of endoplasmic reticulum Ca2+ stores and binds and activates Orai channels in the plasma membrane. This inside-out mechanism of Ca2+ signaling raises an interesting question about the evolution of SOCE: How did these two proteins existing in different cellular compartments evolve to interact with each other? We investigated the gating mechanism of Caenorhabditis elegans Orai channels. Our analysis revealed a mechanism of Orai gating by STIM binding to the intracellular 2–3 loop of Orai in C. elegans that is radically different from Orai gating by STIM binding to the N and C termini of Orai in mammals. In addition, we found that the conserved hydrophobic amino acids in the 2–3 loop of Orai1 are important for the oligomerization and gating of channels and are regulated via an intramolecular interaction mechanism mediated by the N and C termini of Orai1. This study identifies a previously unknown SOCE mechanism in C. elegans and suggests that, while the STIM–Orai interaction is conserved between invertebrates and mammals, the gating mechanism for Orai channels differs considerably.

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