Genetic Cascades Research Articles

Blood-Based Molecular Biomarkers as Predictors for Respiratory Distress Syndrome in Infants of Diabetic Mothers

Abstract Background Respiratory distress (RD) is a primary cause of sickness and mortality in newborns. There is a suggested association between maternal diabetes and respiratory distress in their children, which is directly tied to metabolic and genetic cascades of modifications linked to fetal hyperglycemia. Aim To investigate the circulating expression level of surfactant-related mRNA surfactant protein C (SP-C) in neonates born to diabetic mothers and to compare them with healthy newborns. In addition, to evaluate the clinical utility of the above- mentioned circulating biomarker in predicting the development and severity of RD in infants of diabetic mothers. Patients and Methods This study was conducted on 66 neonates; 23 neonates of infants of diabetic mothers (IDM) who developed respiratory distress after birth, another group of IDMs who did not develop RD, and a control group of 20 healthy neonates. All neonates were subjected to history taking, Full clinical examination, Biochemical tests, Imaging, gene expression analysis, and assessment of hypoglycemia and degree of respiratory distress in IDMs. Results No significant difference was detected in the expression of the SP-C between the IDM group and the healthy group (p = 0.09). However, there was a significant difference between the different degrees of RD (P = 0.04). Conclusion SP-C expression level couldn’t be used as a diagnostic biomarker for RD in IDMs. However, it could be used as a prognostic marker to predict the severity of respiratory distress.

Exuberant circumferential fibroproliferative neuromas in lipomatosis of nerve: a unifying theory. Illustrative case.

Lipomatosis of nerve (LN) is a rare disorder characterized by the massive enlargement of peripheral nerves, frequently accompanied by generalized fibroadipose proliferation and skeletal overgrowth. The authors have been routinely following a 20-year-old male for lipomatosis of median nerve at the wrist noted shortly after birth. He had undergone resection of the lesion accompanied by sural nerve grafting at another institution. Clinically, although his neurological loss of function has been stable, he has had continued soft tissue growth. Serial magnetic resonance imaging has revealed persistent LN proximal to the repair sites with evidence of fatty proliferation in the sural grafts and continued LN and fatty proliferation distally. There has been a progressive circumferential pattern of fibrosis around the proximal and distal suture lines, which has a similar radiological pattern to desmoid type fibromatosis (a pattern recently described in neuromuscular choristoma [NMC] desmoid-type fibromatosis). Considering the similar reaction of nerve in both LN and NMC despite differing genetic cascades, the authors believe a unifying process occurs in both lesions. The pattern of circumferential fibroproliferation would be most consistent with neuron-mediated growth from unspecified trophic factors, supporting a previously reported a nerve-derived "inside-out mechanism." The clinical consequences of this unifying process are presented.

Fgf9-Nolz-1-Wnt2 Axis Regulates Morphogenesis of the Lung.

Morphological development of the lung requires complex signal crosstalk between the mesenchymal and epithelial progenitors. Elucidating the genetic cascades underlying the signal crosstalk is essential to understanding lung morphogenesis. Here, we identified Nolz-1/Znf503 as a mesenchymal lineage-specific transcriptional regulator that plays a key role in lung morphogenesis. Nolz-1 null mutation resulted in a severe hypoplasia phenotype, including a decreased proliferation of mesenchymal cells, aberrant differentiation of epithelial cells, and defective growth of epithelial branches. Nolz-1 deletion also downregulated Wnt2, Lef1, Fgf10, Gli3 and Bmp4 mRNAs. Mechanistically, Nolz-1 regulated lung morphogenesis primarily through Wnt2 signaling. Loss of function and overexpression studies demonstrated that Nolz-1 transcriptionally activated Wnt2 and downstream β-catenin signaling to control mesenchymal cell proliferation and epithelial branching. Exogenous Wnt2 could causally rescue defective proliferation and epithelial branching in Nolz-1 knockout lungs. Finally, we identified Fgf9 as an upstream regulator of Nolz-1. Collectively, Fgf9-Nolz-1-Wnt2 signaling represents a novel axis in the control of lung morphogenesis. These findings are relevant to lung tumorigenesis in which a pathological function of Nolz-1 is implicated.

The Developmental Implications of Muscle-Targeted Magnetic Mitohormesis: A Human Health and Longevity Perspective.

Muscle function reflects muscular mitochondrial status, which, in turn, is an adaptive response to physical activity, representing improvements in energy production for de novo biosynthesis or metabolic efficiency. Differences in muscle performance are manifestations of the expression of distinct contractile-protein isoforms and of mitochondrial-energy substrate utilization. Powerful contractures require immediate energy production from carbohydrates outside the mitochondria that exhaust rapidly. Sustained muscle contractions require aerobic energy production from fatty acids by the mitochondria that is slower and produces less force. These two patterns of muscle force generation are broadly classified as glycolytic or oxidative, respectively, and require disparate levels of increased contractile or mitochondrial protein production, respectively, to be effectively executed. Glycolytic muscle, hence, tends towards fibre hypertrophy, whereas oxidative fibres are more disposed towards increased mitochondrial content and efficiency, rather than hypertrophy. Although developmentally predetermined muscle classes exist, a degree of functional plasticity persists across all muscles post-birth that can be modulated by exercise and generally results in an increase in the oxidative character of muscle. Oxidative muscle is most strongly correlated with organismal metabolic balance and longevity because of the propensity of oxidative muscle for fatty-acid oxidation and associated anti-inflammatory ramifications which occur at the expense of glycolytic-muscle development and hypertrophy. This muscle-class size disparity is often at odds with common expectations that muscle mass should scale positively with improved health and longevity. Brief magnetic-field activation of the muscle mitochondrial pool has been shown to recapitulate key aspects of the oxidative-muscle phenotype with similar metabolic hallmarks. This review discusses the common genetic cascades invoked by endurance exercise and magnetic-field therapy and the potential physiological differences with regards to human health and longevity. Future human studies examining the physiological consequences of magnetic-field therapy are warranted.

Overlapping functions of SIX homeoproteins during embryonic myogenesis.

Four SIX homeoproteins display a combinatorial expression throughout embryonic developmental myogenesis and they modulate the expression of the myogenic regulatory factors. Here, we provide a deep characterization of their role in distinct mouse developmental territories. We showed, at the hypaxial level, that the Six1:Six4 double knockout (dKO) somitic precursor cells adopt a smooth muscle fate and lose their myogenic identity. At the epaxial level, we demonstrated by the analysis of Six quadruple KO (qKO) embryos, that SIX are required for fetal myogenesis, and for the maintenance of PAX7+ progenitor cells, which differentiated prematurely and are lost by the end of fetal development in qKO embryos. Finally, we showed that Six1 and Six2 are required to establish craniofacial myogenesis by controlling the expression of Myf5. We have thus described an unknown role for SIX proteins in the control of myogenesis at different embryonic levels and refined their involvement in the genetic cascades operating at the head level and in the genesis of myogenic stem cells.

An Update on the Molecular Mechanism of the Vertebrate Isthmic Organizer Development in the Context of the Neuromeric Model.

A crucial event during the development of the central nervous system (CNS) is the early subdivision of the neural tube along its anterior-to-posterior axis to form neuromeres, morphogenetic units separated by transversal constrictions and programed for particular genetic cascades. The narrower portions observed in the developing neural tube are responsible for relevant cellular and molecular processes, such as clonal restrictions, expression of specific regulatory genes, and differential fate specification, as well as inductive activities. In this developmental context, the gradual formation of the midbrain-hindbrain (MH) constriction has been an excellent model to study the specification of two major subdivisions of the CNS containing the mesencephalic and isthmo-cerebellar primordia. This MH boundary is coincident with the common Otx2-(midbrain)/Gbx2-(hindbrain) expressing border. The early interactions between these two pre-specified areas confer positional identities and induce the generation of specific diffusible morphogenes at this interface, in particular FGF8 and WNT1. These signaling pathways are responsible for the gradual histogenetic specifications and cellular identity acquisitions with in the MH domain. This review is focused on the cellular and molecular mechanisms involved in the specification of the midbrain/hindbrain territory and the formation of the isthmic organizer. Emphasis will be placed on the chick/quail chimeric experiments leading to the acquisition of the first fate mapping and experimental data to, in this way, better understand pioneering morphological studies and innovative gain/loss-of-function analysis.

Epistatic Interaction and Causal Genetic Mediation in Abdominal Aortic Aneurysm Pathogenesis: Abdominal Aortic Aneurysms

Introduction: Whereas previous studies have shown associations between candidate genes polymorphisms and abdominal aortic aneurysms (AAAs), it is notable that genetic information cascades through multiple complex signalling molecular pathways. There is further evidence to suggest that some of these pathways are shared by many genetic and non-genetic risk factors leading to emergent pathological processes that underlie AAA pathogenesis. The aim of this study was to identify a causal interaction between the ACE insertion/deletion (I/D) and MTHFR C677T genetic polymorphisms in AAA pathogenesis.

Patterning with clocks and genetic cascades: Segmentation and regionalization of vertebrate versus insect body plans.

Oscillatory and sequential processes have been implicated in the spatial patterning of many embryonic tissues. For example, molecular clocks delimit segmental boundaries in vertebrates and insects and mediate lateral root formation in plants, whereas sequential gene activities are involved in the specification of regional identities of insect neuroblasts, vertebrate neural tube, vertebrate limb, and insect and vertebrate body axes. These processes take place in various tissues and organisms, and, hence, raise the question of what common themes and strategies they share. In this article, we review 2 processes that rely on the spatial regulation of periodic and sequential gene activities: segmentation and regionalization of the anterior–posterior (AP) axis of animal body plans. We study these processes in species that belong to 2 different phyla: vertebrates and insects. By contrasting 2 different processes (segmentation and regionalization) in species that belong to 2 distantly related phyla (arthropods and vertebrates), we elucidate the deep logic of patterning by oscillatory and sequential gene activities. Furthermore, in some of these organisms (e.g., the fruit fly Drosophila), a mode of AP patterning has evolved that seems not to overtly rely on oscillations or sequential gene activities, providing an opportunity to study the evolution of pattern formation mechanisms.

Integrative genomic analysis of early neurogenesis reveals a temporal genetic program for differentiation and specification of preplate and Cajal-Retzius neurons.

Neurogenesis in the developing neocortex begins with the generation of the preplate, which consists of early-born neurons including Cajal-Retzius (CR) cells and subplate neurons. Here, utilizing the Ebf2-EGFP transgenic mouse in which EGFP initially labels the preplate neurons then persists in CR cells, we reveal the dynamic transcriptome profiles of early neurogenesis and CR cell differentiation. Genome-wide RNA-seq and ChIP-seq analyses at multiple early neurogenic stages have revealed the temporal gene expression dynamics of early neurogenesis and distinct histone modification patterns in early differentiating neurons. We have identified a new set of coding genes and lncRNAs involved in early neuronal differentiation and validated with functional assays in vitro and in vivo. In addition, at E15.5 when Ebf2-EGFP+ cells are mostly CR neurons, single-cell sequencing analysis of purified Ebf2-EGFP+ cells uncovers molecular heterogeneities in CR neurons, but without apparent clustering of cells with distinct regional origins. Along a pseudotemporal trajectory these cells are classified into three different developing states, revealing genetic cascades from early generic neuronal differentiation to late fate specification during the establishment of CR neuron identity and function. Our findings shed light on the molecular mechanisms governing the early differentiation steps during cortical development, especially CR neuron differentiation.

Cytoskeletal mechanics and dynamics in the Drosophila syncytial embryo.

Cell and tissue functions rely on the genetic programmes and cascades of biochemical signals. It has become evident during the past decade that the physical properties of soft material that govern the mechanics of cells and tissues play an important role in cellular function and morphology. The biophysical properties of cells and tissues are determined by the cytoskeleton, consisting of dynamic networks of F-actin and microtubules, molecular motors, crosslinkers and other associated proteins, among other factors such as cell-cell interactions. The Drosophila syncytial embryo represents a simple pseudo-tissue, with its nuclei orderly embedded in a structured cytoskeletal matrix at the embryonic cortex with no physical separation by cellular membranes. Here, we review the stereotypic dynamics and regulation of the cytoskeleton in Drosophila syncytial embryos and how cytoskeletal dynamics underlies biophysical properties and the emergence of collective features. We highlight the specific features and processes of syncytial embryos and discuss the applicability of biophysical approaches.

Developmental Genes and Malformations in the Hypothalamus.

The hypothalamus is a heterogeneous rostral forebrain region that regulates physiological processes essential for survival, energy metabolism, and reproduction, mainly mediated by the pituitary gland. In the updated prosomeric model, the hypothalamus represents the rostralmost forebrain, composed of two segmental regions (terminal and peduncular hypothalamus), which extend respectively into the non-evaginated preoptic telencephalon and the evaginated pallio-subpallial telencephalon. Complex genetic cascades of transcription factors and signaling molecules rule their development. Alterations of some of these molecular mechanisms acting during forebrain development are associated with more or less severe hypothalamic and pituitary dysfunctions, which may be associated with brain malformations such as holoprosencephaly or septo-optic dysplasia. Studies on transgenic mice with mutated genes encoding critical transcription factors implicated in hypothalamic-pituitary development are contributing to understanding the high clinical complexity of these pathologies. In this review article, we will analyze first the complex molecular genoarchitecture of the hypothalamus resulting from the activity of previous morphogenetic signaling centers and secondly some malformations related to alterations in genes implicated in the development of the hypothalamus.

Molecular mechanisms in grass-Epichloë interactions: towards endophyte driven farming to improve plant fitness and immunity.

All plants harbor many microbial species including bacteria and fungi in their tissues. The interactions between the plant and these microbes could be symbiotic, mutualistic, parasitic or commensalistic. Mutualistic microorganisms are endophytic in nature and are known to play a role in plant growth, development and fitness. Endophytes display complex diversity depending upon the agro-climatic conditions and this diversity could be exploited for crop improvement and sustainable agriculture. Plant-endophyte partnerships are highly specific, several genetic and molecular cascades play a key role in colonization of endophytes in host plants leading to rapid changes in host and endophyte metabolism. This results in the accumulation of secondary metabolites, which play an important role in plant defense against biotic and abiotic stress conditions. Alkaloids are one of the important class of metabolites produced by Epichloë genus and other related classes of endophytes and confer protection against insect and mammalian herbivory. In this context, this review discusses the evolutionary aspects of the Epichloë genus along with key molecular mechanisms determining the lifestyle of Epichloë endophytes in host system. Novel hypothesis is proposed to outline the initial cellular signaling events during colonization of Epichloë in cool season grasses. Complex clustering of alkaloid biosynthetic genes and molecular mechanisms involved in the production of alkaloids have been elaborated in detail. The natural defense and advantages of the endophyte derived metabolites have also been extensively discussed. Finally, this review highlights the importance of endophyte-arbitrated plant immunity to develop novel approaches for eco-friendly agriculture.

Evolutionary developmental genetics of teeth and odontodes in jawed vertebrates: a perspective from the study of elasmobranchs.

Most extant vertebrates display a high variety of tooth and tooth-like organs (odontodes) that vary in shape, position over the body and nature of composing tissues. The development of these structures is known to involve similar genetic cascades and teeth and odontodes are believed to share a common evolutionary history. Gene expression patterns have previously been compared between mammalian and teleost tooth development but we highlight how the comparative framework was not always properly defined to deal with different tooth types or tooth developmental stages. Larger-scale comparative analyses also included cartilaginous fishes: sharks display oral teeth and dermal scales for which the gene expression during development started to be investigated in the small-spotted catshark Scyliorhinus canicula during the past decade. We report several descriptive approaches to analyse the embryonic tooth and caudal scale gene expressions in S. canicula. We compare these expressions wih the ones reported in mouse molars and teleost oral and pharyngeal teeth and highlight contributions and biases that arise from these interspecific comparisons. We finally discuss the evolutionary processes that can explain the observed intra and interspecific similarities and divergences in the genetic cascades involved in tooth and odontode development in jawed vertebrates.

Left-right asymmetric heart jogging increases the robustness of dextral heart looping in zebrafish

Building a left-right (L-R) asymmetric organ requires asymmetric information. This comes from various sources, including asymmetries in embryo-scale genetic cascades (including the left-sided Nodal cascade), organ-intrinsic mechanical forces, and cell-level chirality, but the relative influence of these sources and how they collaborate to drive asymmetric morphogenesis is not understood. During zebrafish heart development, the linear heart tube extends to the left of the midline in a process known as jogging. The jogged heart then undergoes dextral (i.e. rightward) looping to correctly position the heart chambers relative to one another. Left lateralized jogging is governed by the left-sided expression of Nodal in mesoderm tissue, while looping laterality is mainly controlled by heart-intrinsic cell-level asymmetries in the actomyosin cytoskeleton. The purpose of lateralized jogging is not known. Moreover, after jogging, the heart tube returns to an almost midline position and so it is not clear whether or how jogging may impact the dextral loop. Here, we characterize a novel loss-of-function mutant in the zebrafish Nodal homolog southpaw (spaw) that appears to be a true null. We then assess the relationship between jogging and looping laterality in embryos lacking asymmetric Spaw signals. We found that the probability of a dextral loop occurring, does not depend on asymmetric Spaw signals per se, but does depend on the laterality of jogging. Thus, we conclude that the role of leftward jogging is to spatially position the heart tube in a manner that promotes robust dextral looping. When jogging laterality is abnormal, the robustness of dextral looping decreases. This establishes a cooperation between embryo-scale Nodal-dependent L-R asymmetries and organ-intrinsic cellular chirality in the control of asymmetric heart morphogenesis and shows that the transient laterality of the early heart tube has consequences for later heart morphogenetic events.

Prospects for marker-associated selection in tomato <i>Solanum lycopersicum</i> L.

The review gives a brief description of tomato, one of the main objects of olericulture for Siberia. The data on the main directions in the breeding of this culture, such as resistance to various pathogens, the nutritional properties of fruits, the timing of their maturation and storage are generalized. A separate chapter is devoted to the use of various types of DNA markers for constructing detailed genetic maps of the specified object, which, along with full-genome sequencing data, can be used to screen for genes responsible for breeding traits. Most of these traits, especially specific resistance to one or another pathogen, were transferred to the cultivated tomato by crossing with wild species, therefore, special attention was paid in the article to identifying and marking resistance genes to a variety of viral, fungal and bacterial pathogens occurring in Western Siberia and adjacent areas. Another important aspect for breeding is the nutrient content of tomato fruits, including carotenoids, vitamins, sugars, organic acids, etc. Recently, due to modern technologies of sequencing, SNP-genotyping, the development of new bioinformatic approaches, it has become possible to establish genetic cascades determining the biochemical composition of tomato fruits, to identify key genes that can be used in the future for marker-associated selection of nutritional value. And, finally, genetic works devoted to the problem of the optimal dates of fruit ripening in certain climatic conditions and their prolonged storage without loss of quality are discussed.

The Role of Non-Coding RNA in Congenital Heart Diseases.

Cardiovascular development is a complex developmental process starting with the formation of an early straight heart tube, followed by a rightward looping and the configuration of atrial and ventricular chambers. The subsequent step allows the separation of these cardiac chambers leading to the formation of a four-chambered organ. Impairment in any of these developmental processes invariably leads to cardiac defects. Importantly, our understanding of the developmental defects causing cardiac congenital heart diseases has largely increased over the last decades. The advent of the molecular era allowed to bridge morphogenetic with genetic defects and therefore our current understanding of the transcriptional regulation of cardiac morphogenesis has enormously increased. Moreover, the impact of environmental agents to genetic cascades has been demonstrated as well as of novel genomic mechanisms modulating gene regulation such as post-transcriptional regulatory mechanisms. Among post-transcriptional regulatory mechanisms, non-coding RNAs, including therein microRNAs and lncRNAs, are emerging to play pivotal roles. In this review, we summarize current knowledge on the functional role of non-coding RNAs in distinct congenital heart diseases, with particular emphasis on microRNAs and long non-coding RNAs.

Defining developmental diversification of diencephalon neurons through single cell gene expression profiling.

The embryonic diencephalon forms integration centers and relay stations in the forebrain. Anecdotal expression studies suggest that the diencephalon contains multiple developmental compartments and subdivisions. Here, we utilized single cell RNA sequencing to profile transcriptomes of dissociated cells from the diencephalon of E12.5 mouse embryos. We identified the divergence of different progenitors, intermediate progenitors, and emerging neurons. By mapping the identified cell groups to their spatial origins, we characterized the molecular features of cell types and cell states arising from various diencephalic domains. Furthermore, we reconstructed the developmental trajectory of distinct cell lineages, and thereby identified the genetic cascades and gene regulatory networks underlying the progression of the cell cycle, neurogenesis and cellular diversification. The analysis provides new insights into the molecular mechanisms underlying the amplification of intermediate progenitor cells in the thalamus. The single cell-resolved trajectories not only confirm a close relationship between the rostral thalamus and prethalamus, but also uncover an unexpected close relationship between the caudal thalamus, epithalamus and rostral pretectum. Our data provide a useful resource for systematic studies of cell heterogeneity and differentiation kinetics within the diencephalon.

HD-Zip Genes and Their Role in Plant Adaptation to Environmental Factors

This review presents characteristics of the HD-Zip family of homeobox-containing genes unique to plants, and their involvement in molecular mechanisms of resistance to certain adverse environmental factors (such as drought, deficiency of light, and pathogens) is considered. The importance of the HD-Zip genes in modulating and combining the signals from different hormone-dependent genetic cascades controlling the adaptation of plants to various external factors is demonstrated.

Homeogene emx1 is required for nephron distal segment development in zebrafish

Vertebrate kidneys contain nephron functional units where specialized epithelial cell types are organized into segments with discrete physiological roles. Many gaps remain in our understanding of how segment regions develop. Here, we report that the transcription factor empty spiracles homeobox gene 1 (emx1) is a novel nephron segment regulator during embryonic kidney development in zebrafish. emx1 loss of function altered the domains of distal segments without changes in cell turnover or traits like size and morphology, indicating that emx1 directs distal segment fates during nephrogenesis. In exploring how emx1 influences nephron patterning, we found that retinoic acid (RA), a morphogen that induces proximal and represses distal segments, negatively regulates emx1 expression. Next, through a series of genetic studies, we found that emx1 acts downstream of a cascade involving mecom and tbx2b, which encode essential distal segment transcription factors. Finally, we determined that emx1 regulates the expression domains of irx3b and irx1a to control distal segmentation, and sim1a to control corpuscle of Stannius formation. Taken together, our work reveals for the first time that emx1 is a key component of the pronephros segmentation network, which has implications for understanding the genetic regulatory cascades that orchestrate vertebrate nephron patterning.

Frailty and Caenorhabditis elegans as a Benchtop Animal Model for Screening Drugs Including Natural Herbs.

Caenorhabditis elegans has been used in research for years to clarify the genetic cascades and molecular mechanisms of aging, longevity, and health span. Health span is closely related to frailty; however, frailty has a different concept and is evaluated using various parameters in humans, such as Fried's Frailty Criteria. The C. elegans model has several advantages when performing a chemical screen to identify drug candidates. Several mouse models of frailty were recently developed, including a homozygous IL-10 knockout. These mouse models are useful for understanding human frailty; however, they are not appropriate for primary drug screening because they require large spaces, expensive cost, and time consuming assessments. Therefore, a combination of these models may be a promising tool for discovering drugs and understanding the mechanisms of frailty. In addition, natural products, and herbs are attractive sources of novel drugs with pharmacological activity and low toxicity, in fact, over 60% of currently-available drugs are estimated to be related to natural compounds. In this review, the possibility of identifying natural agents (i.e., herb extracts and compounds) that could improve frailty are proposed, and the advantages and limitations of these models are also discussed.