The role of imprinted genes in fetal growth abnormalities

Epigenetics, and in particular imprinted genes, have a critical role in the development and function of the placenta, which in turn has a central role in the regulation of fetal growth and development. A unique characteristic of imprinted genes is their expression from only one allele, maternal or paternal and dependent on parent of origin. This unique expression pattern may have arisen as a mechanism to control the flow of nutrients from the mother to the fetus, with maternally expressed imprinted genes reducing the flow of resources and paternally expressed genes increasing resources to the fetus. As a result, any epigenetic deregulation affecting this balance can result in fetal growth abnormalities. Imprinting-associated disorders in humans, such as Beckwith-Wiedemann and Angelman syndrome, support the role of imprinted genes in fetal growth. Similarly, assisted reproductive technologies in animals have been shown to affect the epigenome of the early embryo and the expression of imprinted genes. Their role in disorders such as intrauterine growth restriction appears to be more complex, in that imprinted gene expression can be seen as both causative and protective of fetal growth restriction. This protective or compensatory effect needs to be explored more fully.     

Genetic and environmental influences on human birth weight

Path-analytic techniques were used to demonstrate a significant influence of both fetal genes and maternal environment on birth weight in a sample of infants born to primarily white, middle-class, nonsmoking mothers. If the mother smoked before conception, however, the expression of the fetal birth-weight genes in males was significantly reduced. Multiparity was associated with an increase in genetic variance. This is the first report that genetic influences on birth weight are dependent on the environmental conditions imposed on the fetus by the mother.     

Prenatal programing: At the intersection of maternal stress and immune activation

This article is part of a Special Issue "Neuroendocrine-Immune Axis in Health and Disease." Exposure to prenatal insults such as maternal stress and pathogenic infections has been associated with an increased risk for neurodevelopmental disorders. The mechanisms by which these programing events occur likely involve complex interactions between the maternal hormonal milieu, the placenta, and the developing fetus, in addition to compounding factors such as fetal sex and gestational stage of development. Despite the diverse biological processes involved, examination of common pathways in maternal stress and immune activation offers intriguing possibilities for elucidation of mechanistic insight. Further, the endocrine and sex-specific placenta is a tissue poised to be a key mediator in fetal programing, located at the intersection of the maternal and embryonic environments. In this review, we will discuss the potential shared mechanisms of maternal stress and immune pathway activation, with a particular focus on the important contribution and role of the placenta. This article is part of a Special Issue entitled (The Neuroendocrine-Immune).     

Developmental origins of variation in human hand preference

Though right-handedness is a prominant characteristic within all human societies, a substantial and stable proportion of individuals are left-handed. Any comprehensive approach to the origin of variation in handedness must account for substantial evidence that left-handedness is associated with reduced fitness, neurodevelopmental disorders, and reduced neuroanatomical asymmetry. In this paper we investigate the hypothesis that developmental instability in early fetal development underlies variation in handedness. In two studies we note an increased incidence of minor physical anomalies (MPAs) and fluctuating asymmetries in both left-handers and extreme right-handers. Moreover, extreme right-handers were more apt to have left-handed parents than moderate right-handers. These data suggest that deviation from moderate right-handedness reflect imprecise expression of a near-universal design due to developmental instability. Preliminary attempts to elucidate the mechanisms underlying developmental instability suggest that both polygenic homozygosity and particular HLA alleles may be important factors. These observations are discussed with respect to current genetic theories of handedness and human evolution.     

Placental regulation of maternal-fetal interactions and brain development

A variety prenatal insults are associated with the incidence of neurodevelopmental disorders such as schizophrenia, autism and cerebral palsy. While the precise mechanisms underlying how transient gestational challenges can lead to later life dysfunctions are largely unknown, the placenta is likely to play a key role. The literal interface between maternal and fetal cells resides in the placenta, and disruptions to the maternal or intrauterine environment are necessarily conveyed to the developing embryo via the placenta. Placental cells bear the responsibility of promoting maternal tolerance of the semiallogeneic fetus and regulating selective permeability of nutrients, gases, and antibodies, while still providing physiological protection of the embryo from adversity. The placenta's critical role in modulating immune protection and the availability of nutrients and endocrine factors to the offspring implicates its involvement in autoimmunity, growth restriction and hypoxia, all factors associated with the development of neurological complications. In this review, we summarize primary maternal-fetal interactions that occur in the placenta and describe pathways by which maternal insults can impair these processes and disrupt fetal brain development. We also review emerging evidence for placental dysfunction in the prenatal programming of neurodevelopmental disorders. ? 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012.     

Timed maternal melatonin treatment reverses circadian disruption of the fetal adrenal clock imposed by exposure to constant light

Surprisingly, in our modern 24/7 society, there is scant information on the impact of developmental chronodisruption like the one experienced by shift worker pregnant women on fetal and postnatal physiology. There are important differences between the maternal and fetal circadian systems; for instance, the suprachiasmatic nucleus is the master clock in the mother but not in the fetus. Despite this, several tissues/organs display circadian oscillations in the fetus. Our hypothesis is that the maternal plasma melatonin rhythm drives the fetal circadian system, which in turn relies this information to other fetal tissues through corticosterone rhythmic signaling. The present data show that suppression of the maternal plasma melatonin circadian rhythm, secondary to exposure of pregnant rats to constant light along the second half of gestation, had several effects on fetal development. First, it induced intrauterine growth retardation. Second, in the fetal adrenal in vivo it markedly affected the mRNA expression level of clock genes and clock-controlled genes as well as it lowered the content and precluded the rhythm of corticosterone. Third, an altered in vitro fetal adrenal response to ACTH of both, corticosterone production and relative expression of clock genes and steroidogenic genes was observed. All these changes were reversed when the mother received a daily dose of melatonin during the subjective night; supporting a role of melatonin on overall fetal development and pointing to it as a 'time giver' for the fetal adrenal gland. Thus, the present results collectively support that the maternal circadian rhythm of melatonin is a key signal for the generation and/or synchronization of the circadian rhythms in the fetal adrenal gland. In turn, low levels and lack of a circadian rhythm of fetal corticosterone may be responsible of fetal growth restriction; potentially inducing long term effects in the offspring, possibility that warrants further research.     

The neurobiological context of autism

Autistic disorder (AD) is a complex neuropsychiatric disorder of neurodevelopmental origin, where multiple genetic and environmental factors may interact, resulting in a clinical continuum. The genetic component is best described by a multilocus model that takes into account epistatic interactions between several susceptibility genes. In the past ten years enormous progress has been made in identifying chromosomal regions in linkage with AD, but moving from chromosomal regions to candidate genes has proven to be tremendously difficult. Neuroanatomical findings point to early dysgenetic events taking place in the cerebral cortex, cerebellum, and brainstem. At the cellular level, disease mechanisms may include altered cell migration, increased cell proliferation, decreased cell death, or altered synapse elimination. Neurochemical findings in AD point to involvement of multiple neurotransmitter systems. The serotoninergic system has been intensively investigated in AD, but other neurotransmitter systems (e.g., the GABAergic and the cholinergic system) are also coming under closer scrutiny. The role of environmental factors is still poorly characterized. It is not clear yet whether environmental factors act merely as precipitating agents, always requiring an underlying genetic liability, or whether they represent an essential component of a pathogenetic process where genetic liability alone does not lead to the full-blown autism phenotype. A third potential player in the pathogenesis of autism, in addition to genetic and environmental factors, is developmental variability due to “random” factors, e.g. small fluctuations of gene expression and complex, non-deterministic interactions between genes during brain development. These considerations suggest that a non-deterministic conceptual framework is highly appropriate for autism research.     

The expectant brain: adapting for motherhood

A successful pregnancy requires multiple adaptations of the mother's physiology to optimize fetal growth and development, to protect the fetus from adverse programming, to provide impetus for timely parturition and to ensure that adequate maternal care is provided after parturition. Many of these adaptations are organized by the mother's brain, predominantly through changes in neuroendocrine systems, and these changes are primarily driven by the hormones of pregnancy. By contrast, adaptations in the mother's brain during lactation are maintained by external stimuli from the young. The changes in pregnancy are not necessarily innocuous: they may predispose the mother to post-partum mood disorders.     

Cell adhesion molecules and their involvement in autism spectrum disorder

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by abnormalities in social interaction, language development and behavior. Recent genetic studies demonstrate that alterations in synaptic genes including those encoding cell adhesion molecules and their interaction partners play important roles in the pathogenesis of ASD. Systematic analyses of different cell adhesion molecule genes will help elucidate their normal functions and regulatory mechanisms in the establishment and maintenance of normal neural circuits and uncover genetic aberrations contributing to ASD.     

Immune Regulation in Eutherian Pregnancy: Live Birth Coevolved with Novel Immune Genes and Gene Regulation

Novel regulatory elements that enabled expression of pre‐existing immune genes in reproductive tissues and novel immune genes with pregnancy‐specific roles in eutherians have shaped the evolution of mammalian pregnancy by facilitating the emergence of novel mechanisms for immune regulation over its course. Trade‐offs arising from conflicting fitness effects on reproduction and host defenses have further influenced the patterns of genetic variation of these genes. These three mechanisms (novel regulatory elements, novel immune genes, and trade‐offs) played a pivotal role in refining the regulation of maternal immune systems during pregnancy in eutherians, likely facilitating the establishment of prolonged direct maternal–fetal contact in eutherians without causing immunological rejection of the genetically distinct fetus.     

Ca2+‐Dependent Hyperpolarization Pathways in Sleep Homeostasis and Mental Disorders

Although we are beginning to understand the neuronal and biochemical nature of sleep regulation, questions remain about how sleep is homeostatically regulated. Beyond its importance in basic physiology, understanding sleep may also shed light on psychiatric and neurodevelopmental disorders. Recent genetic studies in mammals revealed several non‐secretory proteins that determine sleep duration. Interestingly, genes identified in these studies are closely related to psychiatric and neurodevelopmental disorders, suggesting that the sleep‐wake cycle shares some common mechanisms with these disorders. Here we review recent sleep studies, including reverse and forward genetic studies, from the perspectives of sleep duration and homeostasis. We then introduce a recent hypothesis for mammalian sleep in which the fast and slow Ca²⁺‐dependent hyperpolarization pathways are pivotal in generating the SWS firing pattern and regulating sleep homeostasis, respectively. Finally, we propose that these intracellular pathways are potential therapeutic targets for achieving depolarization/hyperpolarization (D/H) balance in psychiatric and neurodevelopmental disorders.     

Maternal-Fetal Interactions and the Maintenance of Hla Polymorphism

There is some empirical evidence that a fetus with an HLA antigen not present in its mother has a higher survival than a fetus sharing antigens with its mother. We have developed both single locus and two-locus theoretical models to examine this mode of selection. First, this immunologically based model appears to have the potential to maintain many alleles at a single locus and to result in an excess of heterozygotes when selection is strong. Second, substantial gametic disequilibrium is maintained between alleles at two loci for this selection mode when recombination is that observed between HLA loci A, B, and DR. Overall, it appears that this mode of selection has the potential to strongly affect genetic variation in the HLA region.     

Using C. elegans to Decipher the Cellular and Molecular Mechanisms Underlying Neurodevelopmental Disorders

Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.     

Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries

Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and?a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.     

Autism Spectrum Disorder Initiation by Inflammation-Facilitated Neurotoxin Transport

Autism spectrum disorders have been linked to genetics, gut microbiota dysbiosis (gut dysbiosis), neurotoxin exposures, maternal allergies or autoimmune diseases. Two barriers to ingested neurotoxin transport into the central nervous system of a fetus or child are the gastrointestinal wall of the mother or child and the blood–brain barrier of the fetus or child. Inflammation from gut dysbiosis or inflammation from a disease or other agent can increase the gastrointestinal wall and the blood–brain barrier permeabilities to enable neurotoxins to reach the brain of a fetus or child. Postnatal gut dysbiosis is a particular inflammation risk for autism spectrum disorders caused by neurotoxin transport into a child's brain. An extensive gut dysbiosis or another source of inflammation such as a disease or other agent in combination with neurotoxins, including aluminum, mercury, lead, arsenic, cadmium, arsenic, organophosphates, and neurotoxic bacterial toxins and fungal toxins resulting from the gut dysbiosis, can elevate neurotoxin levels in a fetal or child brain to cause neurodevelopmental damage and initiate an autism spectrum disorder. The neurotoxins aluminum and mercury are especially synergistic in causing neurodevelopmental damage. There are three plausible causational pathways for autism spectrum disorders. They include inflammation and neurotoxin loading into the fetal brain during the prenatal neurodevelopment period, inflammation and neurotoxin loading into the brain during the postnatal neurodevelopment period or a two-stage loading of neurotoxins into the brain during both the prenatal and postnatal neurodevelopment periods.

     

Genetic Studies of Unusual Loci That Affect Body Shape of the Nematode CAENORHABDITIS ELEGANS and May Code for Cuticle Structural Proteins

In Caenorhabditis elegans, four loci (sqt-1, sqt-2, sqt-3 and rol-8) in which mutations affect body shape and cuticle morphology have unusual genetic properties. Mutant alleles of sqt-1 can interact to produce animals with a variety of mutant phenotypes: left roller, right roller, dumpy and long. At least three mutant phenotypes are specified by mutations in the sqt-3 locus. Most alleles at these loci are either dominant or cryptic dominant (i.e., are dominant only in certain genetic backgrounds). Most alleles of these loci exhibit codominance. Two putative null alleles of the sqt-1 locus produce a wild-type phenotype. Many alleles of these genes demonstrate unusual intergenic interactions that are not the result of simple epistasis: animals doubly heterozygous for mutations at two loci often display unexpected and unpredictable phenotypes. We suggest that these genetic properties might be expected of genes, such as the collagen genes, the products of which interact to form the animal's cuticle, and which are member genes of a gene family.