Organ Asymmetry Research Articles

PKD2: An Important Membrane Protein in Organ Development.

PKD2 was first identified as the pathogenic protein for autosomal dominant polycystic kidney disease (ADPKD) and is widely recognized as an ion channel. Subsequent studies have shown that PKD2 is widely expressed in various animal tissues and plays a crucial role in tissue and organ development. Additionally, PKD2 is conserved from single-celled organisms to vertebrates. Here, we provide an overview of recent advances in the function of PKD2 in key model animals, focusing on the establishment of left-right organ asymmetry, renal homeostasis, cardiovascular development, and signal transduction in reproduction and mating. We specifically focus on the roles of PKD2 in development and highlight future prospects for PKD2 research.

An atypical basement membrane forms a midline barrier during left-right asymmetric gut development in the chicken embryo.

Correct intestinal morphogenesis depends on the early embryonic process of gut rotation, an evolutionarily conserved program in which a straight gut tube elongates and forms into its first loops. However, the gut tube requires guidance to loop in a reproducible manner. The dorsal mesentery (DM) connects the gut tube to the body and directs the lengthening gut into stereotypical loops via left-right (LR) asymmetric cellular and extracellular behavior. The LR asymmetry of the DM also governs blood and lymphatic vessel formation for the digestive tract, which is essential for prenatal organ development and postnatal vital functions including nutrient absorption. Although the genetic LR asymmetry of the DM has been extensively studied, a divider between the left and right DM has yet to be identified. Setting up LR asymmetry for the entire body requires a Lefty1+ midline barrier to separate the two sides of the embryo, without it, embryos have lethal or congenital LR patterning defects. Individual organs including the brain, heart, and gut also have LR asymmetry, and while the consequences of left and right signals mixing are severe or even lethal, organ-specific mechanisms for separating these signals are poorly understood. Here, we uncover a midline structure composed of a transient double basement membrane, which separates the left and right halves of the embryonic chick DM during the establishment of intestinal and vascular asymmetries. Unlike other basement membranes of the DM, the midline is resistant to disruption by intercalation of Netrin4 (Ntn4). We propose that this atypical midline forms the boundary between left and right sides and functions as a barrier necessary to establish and protect organ asymmetry.

The sex of organ geometry

Organs have a distinctive yet often overlooked spatial arrangement in the body1–5. We propose that there is a logic to the shape of an organ and its proximity to its neighbours. Here, by using volumetric scans of many Drosophila melanogaster flies, we develop methods to quantify three-dimensional features of organ shape, position and interindividual variability. We find that both the shapes of organs and their relative arrangement are consistent yet differ between the sexes, and identify unexpected interorgan adjacencies and left–right organ asymmetries. Focusing on the intestine, which traverses the entire body, we investigate how sex differences in three-dimensional organ geometry arise. The configuration of the adult intestine is only partially determined by physical constraints imposed by adjacent organs; its sex-specific shape is actively maintained by mechanochemical crosstalk between gut muscles and vascular-like trachea. Indeed, sex-biased expression of a muscle-derived fibroblast growth factor-like ligand renders trachea sexually dimorphic. In turn, tracheal branches hold gut loops together into a male or female shape, with physiological consequences. Interorgan geometry represents a previously unrecognized level of biological complexity which might enable or confine communication across organs and could help explain sex or species differences in organ function.

Molecular Pathways and Animal Models of Defects in Situs.

Left-right patterning is among the least well understood of the three axes defining the body plan, and yet it is no less important, with left-right patterning defects causing structural birth defects with high morbidity and mortality, such as complex congenital heart disease, biliary atresia, or intestinal malrotation. The cell signaling pathways governing left-right asymmetry are highly conserved and involve multiple components of the TGF-β superfamily of cell signaling molecules. Central to left-right patterning is the differential activation of Nodal on the left, and BMP signaling on the right. In addition, a plethora of other cell signaling pathways including Shh, FGF, and Notch also contribute to the regulation of left-right patterning. In vertebrate embryos such as the mouse, frog, or zebrafish, the specification of left-right identity requires the left-right organizer (LRO) containing cells with motile and primary cilia that mediate the left-sided propagation of Nodal signaling, followed by left-sided activation of Lefty and then Pitx2, a transcription factor that specifies visceral organ asymmetry. While this overall scheme is well conserved, there are striking species differences, including the finding that motile cilia do not play a role in left-right patterning in some vertebrates. Surprisingly, the direction of heart looping, one of the first signs of organ left-right asymmetry, was recently shown to be specified by intrinsic cell chirality, not Nodal signaling, possibly a reflection of the early origin of Nodal signaling in radially symmetric organisms. How this intrinsic chirality interacts with downstream molecular pathways regulating visceral organ asymmetry will need to be further investigated to elucidate how disturbance in left-right patterning may contribute to complex CHD.

Establishment of Cardiac Laterality.

Formation of the vertebrate heart with its complex arterial and venous connections is critically dependent on patterning of the left-right axis during early embryonic development. Abnormalities in left-right patterning can lead to a variety of complex life-threatening congenital heart defects. A highly conserved pathway responsible for left-right axis specification has been uncovered. This pathway involves initial asymmetric activation of a nodal signaling cascade at the embryonic node, followed by its propagation to the left lateral plate mesoderm and activation of left-sided expression of the Pitx2 transcription factor specifying visceral organ asymmetry. Intriguingly, recent work suggests that cardiac laterality is encoded by intrinsic cell and tissue chirality independent of Nodal signaling. Thus, Nodal signaling may be superimposed on this intrinsic chirality, providing additional instructive cues to pattern cardiac situs. The impact of intrinsic chirality and the perturbation of left-right patterning on myofiber organization and cardiac function warrants further investigation. We summarize recent insights gained from studies in animal models and also some human clinical studies in a brief overview of the complex processes regulating cardiac asymmetry and their impact on cardiac function and the pathogenesis of congenital heart defects.

Mapping the Auditory Space of Culex pipiens Female Mosquitoes in 3D.

The task of directional hearing faces most animals that possess ears. They approach this task in different ways, but a common trait is the use of binaural cues to find the direction to the source of sound. In insects, the task is further complicated by their small size and, hence, minute temporal and level differences between two ears. A single symmetric flagellar particle velocity receiver, such as the antenna of a mosquito, should not be able to discriminate between the two opposite directions along the vector of the sound wave. Paired antennae of mosquitoes presume the usage of binaural hearing, but its mechanisms are expected to be significantly different from the ones typical for the pressure receivers. However, the directionality of flagellar auditory organs has received little attention. Here, we measured the in-flight orientation of antennae in female Culex pipiens pipiens mosquitoes and obtained a detailed physiological mapping of the Johnston's organ directionality at the level of individual sensory units. By combining these data, we created a three-dimensional model of the mosquito's auditory space. The orientation of the antennae was found to be coordinated with the neuronal asymmetry of the Johnston's organs to maintain a uniformly shaped auditory space, symmetric relative to a flying mosquito. The overlap of the directional characteristics of the left and right sensory units was found to be optimal for binaural hearing focused primarily in front of, above and below a flying mosquito.

Asymmetric activity of NetrinB controls laterality of the Drosophila brain

Left-Right (LR) asymmetry of the nervous system is widespread across animals and is thought to be important for cognition and behaviour. But in contrast to visceral organ asymmetry, the genetic basis and function of brain laterality remain only poorly characterized. In this study, we performed RNAi screening to identify genes controlling brain asymmetry in Drosophila. We found that the conserved NetrinB (NetB) pathway is required for a small group of bilateral neurons to project asymmetrically into a pair of neuropils (Asymmetrical Bodies, AB) in the central brain in both sexes. While neurons project unilaterally into the right AB in wild-type flies, netB mutants show a bilateral projection phenotype and hence lose asymmetry. Developmental time course analysis reveals an initially bilateral connectivity, eventually resolving into a right asymmetrical circuit during metamorphosis, with the NetB pathway being required just prior symmetry breaking. We show using unilateral clonal analysis that netB activity is required specifically on the right side for neurons to innervate the right AB. We finally show that loss of NetB pathway activity leads to specific alteration of long-term memory, providing a functional link between asymmetrical circuitry determined by NetB and animal cognitive functions.

Actin polymerisation and crosslinking drive left-right asymmetry in single cell and cell collectives

Deviations from mirror symmetry in the development of bilateral organisms are common but the mechanisms of initial symmetry breaking are insufficiently understood. The actin cytoskeleton of individual cells self-organises in a chiral manner, but the molecular players involved remain essentially unidentified and the relationship between chirality of an individual cell and cell collectives is unclear. Here, we analysed self-organisation of the chiral actin cytoskeleton in individual cells on circular or elliptical patterns, and collective cell alignment in confined microcultures. Screening based on deep-learning analysis of actin patterns identified actin polymerisation regulators, depletion of which suppresses chirality (mDia1) or reverses chirality direction (profilin1 and CapZβ). The reversed chirality is mDia1-independent but requires the function of actin-crosslinker α−actinin1. A robust correlation between the effects of a variety of actin assembly regulators on chirality of individual cells and cell collectives is revealed. Thus, actin-driven cell chirality may underlie tissue and organ asymmetry.

Urbanization increases fluctuating asymmetry and affects behavioral traits of a common grasshopper.

Urbanization has a major impact on biodiversity. For many organisms, the urbanization process means environmental stress caused by fragmentation and increased temperatures in cities and atmospheric, soil, light, and noise pollution. Such environmental stress can influence both the morphology and behavior of animals. Hence, individuals might be selected for survival-facilitating traits under high pressures in urban areas. The specific impact of urbanization on insect behavior is still largely unexplored. We studied the impact of urbanization on one of the most common grasshopper species in Germany, Chorthippus biguttulus, by comparing morphological and behavioral traits of individuals sampled from grasslands with low, medium, and high urbanization levels. We first investigated whether urbanization as a stressor affected body size and fluctuating asymmetry in the locomotor organs. Next, we examined whether urbanization induced changes in the individuals' boldness and activity. Our results showed that fluctuating asymmetry of grasshoppers' locomotory organs increased more than twofold with urbanization level. Further, individuals' boldness and walking activity increased from areas with low to high urbanization levels. Our results indicate strong responses of grasshoppers in terms of morphology and behavior to the urban environment. To compensate for urbanization effects on arthropod populations, management strategies need to be developed that maintain ecological processes and reduce environmental stress in urban areas.

Identification of DNAH17 Variants in Han-Chinese Patients With Left–Right Asymmetry Disorders

The formation of left–right asymmetry of the visceral organs is a conserved feature of the human body, and the asymmetry specification of structure and function is precisely orchestrated by multiple regulatory mechanisms. The abnormal results of organ positioning situs arise from defective cilia structure or function during embryogenesis in humans. In this study, we recruited two unrelated Han-Chinese families with left–right asymmetry disorders. The combination of whole-exome sequencing and Sanger sequencing identified two compound heterozygous variants: c.4109C>T and c.9776C>T, and c.612C>G and c.8764C>T in the dynein axonemal heavy chain 17 gene (DNAH17) in two probands with left–right asymmetry disorders. We report for the first time a possible association between DNAH17 gene variants and left–right asymmetry disorders, which is known as a causal gene for asthenozoospermia. Altogether, the findings of our study may enlarge the DNAH17 gene variant spectrum in human left–right asymmetry disorders, pave a way to illustrate the potential pathogenesis of ciliary/flagellar disorders, and provide supplementary explanation for genetic counseling.

Asymmetric architecture is non-random and repeatable in a bird’s nests

Bilateral, or left-right, asymmetry has evolved independently in many life forms and can be randomly, genetically or environmentally determined1. In a population, the frequency of left and right phenotypes can vary randomly or be fixed depending on, for example, their adaptive value1. Bilateral asymmetry has been described and quantified in individual morphological or behavioral traits, such as internal organ asymmetry or handedness1-3, but rarely in extended phenotypes. Bilateral asymmetry is present in animal architecture, such as snail shells or bird nests. How common and important asymmetry is in animal architecture remains to be quantified4. Here, we use a citizen-science approach to quantify the occurrence of left-right asymmetry in the complex nest of a bird, the rufous hornero (Furnarius rufus). We assess the possible evolutionary mechanisms underlying asymmetric nest architecture and predict a genetic underpinning.

Asymmetry of the male internal reproductive organs in Mantophasmatodea

BackgroundAsymmetries are a widespread phenomenon in otherwise bilaterally symmetric organisms, and investigation of asymmetric structures can help us gather insights into fundamental evolutionary processes such as the selection for morphological novelties caused by behavioural changes. In insects, asymmetric genitalia have evolved in almost every order, and usually it’s the sclerotized parts and most conspicuous male phallic organs that are known to exhibit asymmetries. While external copulatory organs in insects have often been subject to investigations concerning asymmetries and the evolution thereof, internal reproductive structures have received far less attention. Here we describe the internal and external male genitalia in three species of Austrophasmatidae, Mantophasmatodea, using μ-CT imaging and light microscopy. Mantophasmatodea is the most recently discovered insect order, and with 21 species described to date, it is among the smallest insect orders currently known.ResultsWe confirm that male heelwalkers exhibit asymmetries in the external genitalia and associated structures, represented by asymmetric phallic lobes and cerci. Moreover, we found an extreme asymmetry within the internal male genitalia: in all adult males investigated (N = 5), the seminal vesicle, a dilatation of the vas deferens, was only developed on the right side of the male while missing on the left side.ConclusionThe false-male-above mating position exhibited by Mantophasmatodea and especially the long copulation duration of ca. 3 days might select for this unusual absence asymmetry of the left seminal vesicle. If this holds true for all heelwalker species, this absence asymmetry constitutes another autapomorphy for Austrophasmatidae or even the insect order Mantophasmatodea.

Vestibular Morphological Asymmetry Associated With Motion Sickness Susceptibility.

Sensory conflicts leading to motion sickness can occur not only between but also within sensory modalities. The vestibular organs are located in both left and right inner ears, and their misalignment can be a source of self-motion related sensory conflicts. In the current study, using inner ear magnetic resonance imaging, we examined whether morphological asymmetry of the bilateral vestibular organs was associated with motion sickness susceptibility. The results showed a larger position asymmetry of bilateral vestibular organs in individuals with high rather than low susceptibility. In addition, vestibular position asymmetry was associated with reciprocal interaction (negative resting state functional connectivity) between vestibular and visuocortical regions in lowly, but not highly, susceptible individuals. In conclusion, these findings suggest that vestibular morphological asymmetry can be a source of sensory conflicts in individuals with dysfunctional reciprocal visuo-vestibular interactions, a putative neural mechanism for resolving sensory conflicts.

Maternal control of visceral asymmetry evolution in Astyanax cavefish

The direction of visceral organ asymmetry is highly conserved during vertebrate evolution with heart development biased to the left and pancreas and liver development restricted to opposing sides of the midline. Here we show that reversals in visceral organ asymmetry have evolved in Astyanax mexicanus, a teleost species with interfertile surface-dwelling (surface fish) and cave-dwelling (cavefish) forms. Visceral organ asymmetry is conventional in surface fish but some cavefish have evolved reversals in heart, liver, and pancreas development. Corresponding changes in the normally left-sided expression of the Nodal-Pitx2/Lefty signaling system are also present in the cavefish lateral plate mesoderm (LPM). The Nodal antagonists lefty1 (lft1) and lefty2 (lft2), which confine Nodal signaling to the left LPM, are expressed in most surface fish, however, lft2, but not lft1, expression is absent during somitogenesis of most cavefish. Despite this difference, multiple lines of evidence suggested that evolutionary changes in L-R patterning are controlled upstream of Nodal-Pitx2/Lefty signaling. Accordingly, reciprocal hybridization of cavefish and surface fish showed that modifications of heart asymmetry are present in hybrids derived from cavefish mothers but not from surface fish mothers. The results indicate that changes in visceral asymmetry during cavefish evolution are influenced by maternal genetic effects.

Bioimpedance analysis of human body composition: medical applications, terminology

To diagnose and dynamically monitor patients with diseases accompanied by changes in body composition, data from a number of hardware analytical methods are required. Non-invasive, without radiation and chemical loads, fast and patientfriendly bioimpedance analysis of body composition comprehensively solves the problem of obtaining quantitative estimates of all components of body composition at the same time.
 This article discusses the terminology features of bioimpedance analysis of body composition and the most common mistakes in the use of terms. In the Russian-speaking medical environment, you can often find the use of a number of inaccurate terms related to bioimpedance analysis of the human body composition. At the same time, the terminology of bioimpedance analysis of human body composition in English-language publications has long been established. The article presents the Russian and English terms of bioimpedance analysis of the human body composition with corresponding abbreviations, as well as the hierarchy of the terms body composition components, body composition parameters, parameters of bioimpedance analysis of body composition and bioimpedance parameters.
 The most developed areas of application of bioimpedance analysis in medical practice are discussed: assessment of nutrition and dynamic observations of changes in body composition, assessment of the body mineral mass, assessment of the body hydration parameters, assessment of blood supply to tissues and organs, including in the monitoring mode, assessment of the asymmetry of paired organs and limbs, assessment of pre-start readiness, physical development and the level of fitness of the athletes muscular system.

Isthmin1, a secreted signaling protein, acts downstream of diverse embryonic patterning centers in development

Extracellular signals play essential roles during embryonic patterning by providing positional information in a concentration-dependent manner, and many such signals, like Wnt, fibroblast growth factor (FGF), Hedgehog (Hh), and retinoic acid, act by being secreted into the extracellular space, thereby triggering receptor-mediated responses in other cells. Isthmin1 (ism1) is a secreted protein whose gene expression pattern coincides with that of early dorsal determinants, nodal ligand genes like sqt and cyc, and with fgf8 during various phases of zebrafish development. Ism1 functions in early embryonic patterning and development are poorly understood; however, it has recently been shown to interact with nodal pathway genes to control organ asymmetry in chicken. Here, we show that misexpression of ism1 deletion constructs disrupts embryonic patterning in zebrafish and exhibits genetic interactions with both Fgf and nodal signaling. Unlike Fgf and nodal pathway mutants, CRISPR/Cas9-engineered ism1 mutants did not show obvious developmental defects. Further, in vivo single molecule fluorescence correlation spectroscopy (FCCS) showed that Ism1 diffuses freely in the extra-cellular space, with a diffusion coefficient similar to that of Fgf8a; however, our measurements do not support direct molecular interactions between Ism1 and either nodal ligands or Fgf8a in the developing zebrafish embryo. Together, data from gain- and loss-of-function experiments suggest that zebrafish Ism1 plays a complex role in regulating extracellular signals during early embryonic development.

Sample Size for Bioindication of Pollution Level by the Method of Fluctuating Asymmetry

Bioindication is a convenient tool for assessing the environmental situation and the level of pollution of natural and man-made landscapes. One of the most important indicator is the fluctuating asymmetry of plant organs, less common – organs of animals and humans. In 2019, we studied the fluctuating asymmetry of Pinus sylvestris L. located in the industrial zone (Yanino-1), as well as in city parks of St. Petersburg (Alexandrino, Sergievka) and Moscow (Sokolniki). The dependence of the fluctuation asymmetry on the sample size is studied, the volumes of samples are substantiated, an algorithm for processing experimental data is proposed, which allows increasing the accuracy of experiments, avoids false positive or false

Epidermal restriction confers robustness to organ shapes.

The shape of comparable tissues and organs is consistent among individuals of a given species, but how this consistency or robustness is achieved remains an open question. The interaction between morphogenetic factors determines organ formation and subsequent shaping, which is ultimately a mechanical process. Using a computational approach, we show that the epidermal layer is essential for the robustness of organ geometry control. Specifically, proper epidermal restriction allows organ asymmetry maintenance, and the tensile epidermal layer is sufficient to suppress local variability in growth, leading to shape robustness. The model explains the enhanced organ shape variations in epidermal mutant plants. In addition, differences in the patterns of epidermal restriction may underlie the initial establishment of organ asymmetry. Our results show that epidermal restriction can answer the longstanding question of how cellular growth noise is averaged to produce precise organ shapes, and the findings also shed light on organ asymmetry establishment.

Phenotypic features of ciliary dyskinesia among patients with congenital cardiovascular malformations.

Cilia are cell membrane-bound organelles responsible for airway mucus clearance, establishment of left-right organ asymmetry, cardiogenesis, and many other functions in utero. Phenotypic features suggestive of respiratory ciliary dyskinesia among patients with heterotaxy syndrome, defined as complex cardiovascular malformations (CVM) and situs ambiguus (SA), has not been adequately explored. We hypothesized that there is a greater incidence of phenotypic features consistent with ciliary dyskinesia among patients with heterotaxy syndrome compared to patients with other CVM and laterality defects without heterotaxy syndrome. Thirty six subjects were identified by medical record search and divided into four groups based on situs status and type of CVM as follows: SA and complex CVM (group 1); SA and simple CVM (group 2); situs solitus and complex CVM (group 3); and situs solitus and simple CVM (group 4). Phenotype was assessed with a clinical questionnaire, nasal nitric oxide (NO) level, and pulmonary function testing. Those with complex CVM underwent additional testing for variants in genes involved in ciliary structure and function. The mean nasal NO level was significantly lower among all subjects with complex CVM regardless of situs anomalies (groups 1 and 3). There was no significant difference in respiratory symptoms or lung function among the four groups. No bi-allelic genetic mutations were detected among patients with complex CVM. This study identified a relatively lower mean nasal NO level, suggestive of relative ciliary dyskinesia, among subjects with complex CVM. Pulmonary function and clinical symptoms did not reflect significant pulmonary disease among those with complex CVM.

MiR-103/107 regulates left-right asymmetry in zebrafish by modulating Kupffer’s vesicle development and ciliogenesis

In zebrafish, cilia movement within the Kupffer’s vesicle (KV) generates a fluid flow responsible for accumulating nodal signals exclusively in the left lateral plate mesoderm, thereby initiating left-right patterning (LRP). Defects in LRP cause devastating congenital disorders including congenital heart malformations due to organ mis-positioning. We identified the miR-103/107 family to be involved in regulating LRP. Depletion of miR-103/107 in zebrafish embryos resulted in malpositioned and malformed visceral organs and hearts due to disturbed LRP gene expression, indicating early defects in LRP. Additionally, loss of miR-103/107 affected KV morphogenesis and cilia formation without disturbing endoderm development. Human fibroblasts depleted of miR-103a/107 often failed to extend cilia or developed shorter cilia, indicating functional conservation between species. We identified arl6, araf and foxH1 as direct targets of miR-103/107 providing a mechanistic link to cilia development and nodal signal titration. We describe a new microRNA family controlling KV development and hence influencing establishment of internal organ asymmetry.