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      Epigenetic regulation of lateralized fetal spinal gene expression underlies hemispheric asymmetries

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          Abstract

          Lateralization is a fundamental principle of nervous system organization but its molecular determinants are mostly unknown. In humans, asymmetric gene expression in the fetal cortex has been suggested as the molecular basis of handedness. However, human fetuses already show considerable asymmetries in arm movements before the motor cortex is functionally linked to the spinal cord, making it more likely that spinal gene expression asymmetries form the molecular basis of handedness. We analyzed genome-wide mRNA expression and DNA methylation in cervical and anterior thoracal spinal cord segments of five human fetuses and show development-dependent gene expression asymmetries. These gene expression asymmetries were epigenetically regulated by miRNA expression asymmetries in the TGF-β signaling pathway and lateralized methylation of CpG islands. Our findings suggest that molecular mechanisms for epigenetic regulation within the spinal cord constitute the starting point for handedness, implying a fundamental shift in our understanding of the ontogenesis of hemispheric asymmetries in humans.

          DOI: http://dx.doi.org/10.7554/eLife.22784.001

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          Most cited references97

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          Survival with an asymmetrical brain: advantages and disadvantages of cerebral lateralization.

          Recent evidence in natural and semi-natural settings has revealed a variety of left-right perceptual asymmetries among vertebrates. These include preferential use of the left or right visual hemifield during activities such as searching for food, agonistic responses, or escape from predators in animals as different as fish, amphibians, reptiles, birds, and mammals. There are obvious disadvantages in showing such directional asymmetries because relevant stimuli may be located to the animal's left or right at random; there is no a priori association between the meaning of a stimulus (e.g., its being a predator or a food item) and its being located to the animal's left or right. Moreover, other organisms (e.g., predators) could exploit the predictability of behavior that arises from population-level lateral biases. It might be argued that lateralization of function enhances cognitive capacity and efficiency of the brain, thus counteracting the ecological disadvantages of lateral biases in behavior. However, such an increase in brain efficiency could be obtained by each individual being lateralized without any need to align the direction of the asymmetry in the majority of the individuals of the population. Here we argue that the alignment of the direction of behavioral asymmetries at the population level arises as an "evolutionarily stable strategy" under "social" pressures occurring when individually asymmetrical organisms must coordinate their behavior with the behavior of other asymmetrical organisms of the same or different species.
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            Effects of the Social Environment and Stress on Glucocorticoid Receptor Gene Methylation: A Systematic Review.

            The early-life social environment can induce stable changes that influence neurodevelopment and mental health. Research focused on early-life adversity revealed that early-life experiences have a persistent impact on gene expression and behavior through epigenetic mechanisms. The hypothalamus-pituitary-adrenal axis is sensitive to changes in the early-life environment that associate with DNA methylation of a neuron-specific exon 17 promoter of the glucocorticoid receptor (GR) (Nr3c1). Since initial findings were published in 2004, numerous reports have investigated GR gene methylation in relationship to early-life experience, parental stress, and psychopathology. We conducted a systematic review of this growing literature, which identified 40 articles (13 animal and 27 human studies) published since 2004. The majority of these examined the GR exon variant 1F in humans or the GR17 in rats, and 89% of human studies and 70% of animal studies of early-life adversity reported increased methylation at this exon variant. All the studies investigating exon 1F/17 methylation in conditions of parental stress (one animal study and seven human studies) also reported increased methylation. Studies examining psychosocial stress and psychopathology had less consistent results, with 67% of animal studies reporting increased exon 17 methylation and 17% of human studies reporting increased exon 1F methylation. We found great consistency among studies investigating early-life adversity and the effect of parental stress, even if the precise phenotype and measures of social environment adversity varied among studies. These results are encouraging and warrant further investigation to better understand correlates and characteristics of these associations.
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              A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans.

              How left/right functional asymmetry is layered on top of an anatomically symmetrical nervous system is poorly understood. In the nematode Caenorhabditis elegans, two morphologically bilateral taste receptor neurons, ASE left (ASEL) and ASE right (ASER), display a left/right asymmetrical expression pattern of putative chemoreceptor genes that correlates with a diversification of chemosensory specificities. Here we show that a previously undefined microRNA termed lsy-6 controls this neuronal left/right asymmetry of chemosensory receptor expression. lsy-6 mutants that we retrieved from a genetic screen for defects in neuronal left/right asymmetry display a loss of the ASEL-specific chemoreceptor expression profile with a concomitant gain of the ASER-specific profile. A lsy-6 reporter gene construct is expressed in less than ten neurons including ASEL, but not ASER. lsy-6 exerts its effects on ASEL through repression of cog-1, an Nkx-type homeobox gene, which contains a lsy-6 complementary site in its 3' untranslated region and that has been shown to control ASE-specific chemoreceptor expression profiles. lsy-6 is the first microRNA to our knowledge with a role in neuronal patterning, providing new insights into left/right axis formation.
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                Author and article information

                Contributors
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                01 February 2017
                2017
                : 6
                : e22784
                Affiliations
                [1 ]deptInstitute of Cognitive Neuroscience, Department Biopsychology , Ruhr University Bochum , Bochum, Germany
                [2 ]deptDepartment of Neuroanatomy and Molecular Brain Research , Ruhr University Bochum , Bochum, Germany
                [3 ]deptDepartment of Genetic Psychology , Ruhr University Bochum , Bochum, Germany
                [4 ]deptDepartment of Obstetrics and Gynecology , St. Johannes Hospital , Dortmund, Germany
                [5 ]deptDepartment of Neurology , University Hospital Bergmannsheil , Bochum, Germany
                [6 ]deptLanguage and Genetics Department , Max Planck Institute for Psycholinguistics , Nijmegen, Netherlands
                [7 ]deptDonders Institute for Brain, Cognition and Behaviour , Radboud University , Nijmegen, Netherlands
                [8 ]deptDepartment of Human Genetics , Ruhr University Bochum , Bochum, Germany
                [9 ]deptStellenbosch Institute for Advanced Study (STIAS) , Wallenberg Research Centre at Stellenbosch University , Stellenbosch, South Africa
                [10]University of Oxford , United Kingdom
                [11]University of Oxford , United Kingdom
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0001-5882-3200
                Article
                22784
                10.7554/eLife.22784
                5295814
                28145864
                8ef67c5c-c23a-4f9c-8252-21d3c0cdfb39
                © 2017, Ocklenburg et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 29 October 2016
                : 31 January 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: Gu227/16-1
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Neuroscience
                Custom metadata
                2.5
                Gene expression asymmetries in fetal spinal cord are triggered by epigenetic mechanisms suggesting that handedness has a spinal instead of a cortical origin.

                Life sciences
                lateralization,spinal cord,epigenetics,human
                Life sciences
                lateralization, spinal cord, epigenetics, human

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