Participation of L-Lactate and Its Receptor HCAR1/GPR81 in Neurovisual Development.

During the development of the retina and the nervous system, high levels of energy are required by the axons of retinal ganglion cells (RGCs) to grow towards their brain targets. This energy demand leads to an increase of glycolysis and L-lactate concentrations in the retina. L-lactate is known to be the endogenous ligand of the GPR81 receptor. However, the role of L-lactate and its receptor in the development of the nervous system has not been studied in depth. In the present study, we used immunohistochemistry to show that GPR81 is localized in different retinal layers during development, but is predominantly expressed in the RGC of the adult rodent. Treatment of retinal explants with L-lactate or the exogenous GPR81 agonist 3,5-DHBA altered RGC growth cone (GC) morphology (increasing in size and number of filopodia) and promoted RGC axon growth. These GPR81-mediated modifications of GC morphology and axon growth were mediated by protein kinases A and C, but were absent in explants from gpr81-/- transgenic mice. Living gpr81-/- mice showed a decrease in ipsilateral projections of RGCs to the dorsal lateral geniculate nucleus (dLGN). In conclusion, present results suggest that L-lactate and its receptor GPR81 play an important role in the development of the visual nervous system.

The ins and outs of maternal-fetal fatty acid metabolism.

Fatty acids (FAs) are one the most essential substances in intrauterine human growth. They are involved in a number of energetic and metabolic processes, including the growth of cell membranes, the retina and the nervous system. Fatty acid deficiency and disruptions in the maternal-placental fetal metabolism of FAs lead to malnutrition of the fetus, hypotrophy and preterm birth. What is more, metabolic diseases and cardiovascular conditions may appear later in life. Meeting a fetus' need for FAs is dependent on maternal diet and on the efficiency of the placenta in transporting FAs to fetal circulation. "Essential fatty acids" are among the most important FAs during the intrauterine growth period. These are α-linolenic acid, which is a precursor of the n-3 series, linoleic acid, which is a precursor of the n-6 series and their derivatives, represented by docosahexaenoic acid and arachidonic acid. The latest studies have shown that medium-chain fatty acids also play a significant role in maternal-fetal metabolism. These FAs have significant effect on the transformation of the precursors into DHA, which may contribute to a relatively stable supply of DHA - even in pregnant women whose diet is low in FAs. The review discusses the problem of fatty acid metabolism at the intersection between a pregnant woman and her child with reference to physiological pregnancy, giving birth to a healthy child, intrauterine growth restriction, preterm birth and giving birth to a small for gestational age child.

The Yin and Yang of Wnt/Ryk axon guidance in development and regeneration.

In the developing embryo, nascent axons navigate towards their specific targets to establish the intricate network of axonal connections linking neurons within the mature nervous system. Molecular navigational systems comprising repulsive and attractive guidance cues form chemotactic gradients along the pathway of the exploring growth cone. Axon-bound receptors detect these gradients and determine the trajectory of the migrating growth cone. In contrast to their benevolent role in the developing nervous system, repulsive guidance receptors are detrimental to the axon's ability to regenerate after injury in the adult. In this review we explore the essential and beneficial role played by the chemorepulsive Wnt receptor, Ryk/Derailed in axon navigation in the embryonic nervous system (the Yin function). Specifically, we focus on the role of Wnt5a/Rykmediated guidance in the establishment of two major axon tracts in the mammalian central nervous system, the corticospinal tract and the corpus callosum. Recent studies have also identified Ryk as a major suppressor of axonal regeneration after spinal cord injury. Thus, we also discuss this opposing aspect of Ryk function in axonal regeneration where its activity is a major impediment to axon regrowth (the Yang function).

[On some features of embryonic development and metamorphosis of Aurelia aurita (Cindaria, Scyphozoa)].

Aurelia aurita is a cosmopolite species of scyphomedusae. Its major structural patterns and life cycle are well investigated. This work provides a detailed study on development and structure of the planula in A. aurita until it completes its metamorphosis. Lifetime observations and histological study performed during the settlement and metamorphosis of the planulae demonstrated that the inner manibrium linen of primary polyp (gastroderm) develops from the ectoderm of the planula posterior end. The spatial and temporal dynamics of serotonergic cells from the early embryonic stages until the formation of the primary polyp were studied for the first time. In addition, the distribution oftyrosinated tubulin and neuropeptide RFamide at different stages ofA. aurita development were studied.

Compound selection for in vitro modeling of developmental neurotoxicity.

Development of in vitro systems, such as those based on embryonic stem cell differentiation, depends on the selection of adequate test and training compounds. We recommend the use of two classes of positive controls, the "gold standard compounds" for which developmental neurotoxicity (DNT) has been proven in man, and the "pathway compounds" that are known to disrupt signalling pathways and key processes relevant for neuronal differentiation. We introduce the concept of toxicity endophenotypes (TEP) as changes in neuronal connectivity resulting from exposure to developmental toxicants. Thus, TEPs provide the scientific rationale for modeling DNT with simple in vitro models of key neurodevelopmental events. In this context, we discuss scientific and technical aspects of the test compound selection process. We suggest to include compounds with unspecific toxicity, besides negative control compounds, and we recommend tandem approaches to determine relative toxicities instead of absolute measures. Finally, we discuss how to avoid pitfalls by distinguishing between unspecific forms of cytotoxicity and specific developmental neurotoxicity. A compilation of compound lists corresponding to the above-discussed principles supplement this review.

Rat models of prenatal and adolescent cannabis exposure.

Marijuana (Cannabis sativa) is the illicit drug most commonly used by two vulnerable populations relevant to neurodevelopment-pregnant women and teenagers. Human longitudinal studies have linked prenatal and adolescent cannabis exposure with long-term behavioral abnormalities as well as increased vulnerability to neuropsychiatric disorders in adulthood. Animal models provide a means of studying the neurobiological mechanisms underlying these long-term effects. This chapter provides an overview of the animal models we have used to study the developmental impact of cannabis.

Effect of heavy oil on the development of the nervous system of floating and sinking teleost eggs.

Heavy oil (HO) on the sea surface penetrates into fish eggs and prevents the normal morphogenesis. To identify the toxicological effects of HO in the context of the egg types, we performed exposure experiments using floating eggs and sinking eggs. In the course of development, HO-exposed embryos of floating eggs showed abnormal morphology, whereas early larva of the sinking eggs had almost normal morphology. However, the developing peripheral nervous system of sinking eggs showed abnormal projections. These findings suggest that HO exposed fishes have problems in the developing neurons, although they have no morphological malformations. Through these observations, we conclude that HO is strongly toxic to floating eggs in the morphogenesis, and also affect the neuron development in both floating and sinking eggs.

Essential fatty acid supplementation of DHA and ARA and effects on neurodevelopment across animal species: a review of the literature.

Docosahexanoic acid (DHA) and arachidonic acid (ARA) are long chain essential fatty acids used as supplements in commercial infant formula. DHA/ARA deficient states are associated with adverse neurological outcomes in animals and humans. Preterm infants are at risk for DHA/ARA deficiency. A few clinical reports on the effects of fatty acid supplementation have shown benefit in preterm, low birth weight, and normal infants in the first year of life, whereas others did not. Studies in animals have reported shortened gestation, fetal growth retardation, reduced infant body mass, and increased fetal mortality with consumption of fatty acids during pregnancy. To understand the data that support fatty acid supplementation in infant formula, a review of the animal model literature was undertaken, to examine the effects of DHA/ARA on neurodevelopment, including the effects on visual acuity. Several points emerged from this review. (1) Animal studies indicate that requirements for DHA/ARA vary depending on developmental age. Alterations of the ratio of DHA/ARA can impact developmental outcome. (2) The available studies suggest that while supplementation of DHA/ARA in an appropriate ratio can increase tissue levels of these fatty acids in the brain and retina, tissues sensitive to depletion of fatty acids, the benefit of routine supplementation remains unclear. Few studies measure functional outcome relative to changes in physiologic pools of DHA/ARA after supplementation. (3) Animal literature does not support a clear long-term benefit of replenishing DHA/ARA tissue levels and administration of these fatty acids at concentrations above those in human milk suggests adverse effects on growth, survival, and neurodevelopment.

[Fetal and perinatal exposure to mercury and selenium: baseline evaluation of a cohort of children in Friuli Venezia Giulia, Italy]. / Esposizione fetale e perinatale a mercurio e selenio: valutazione alla baseline di una coorte di bambini del Friuli Venezia Giulia.

OBJECTIVE: neurotoxicity of prenatal exposure to high concentrations of mercury (Hg) is well known; however, the doseresponse relationship at low exposure levels has not been quantified yet. This article illustrates the measurement of prenatal exposure to Hg and the pathway of exposure through the diet in Friuli Venezia Giulia, Italy. DESIGN: description of a prospective cohort at the baseline. SETTING AND PARTICIPANTS: 242 mother- infant pairs living in Friuli Venezia Giulia were enrolled between 1999 and 2001. MAIN OUTCOME MEASURES: We measured the concentrations of Hg in the hair of mothers and children and of Hg and selenium (Se) in breast milk. The diet during pregnancy was estimated through a food frequency questionnaire (FFQ) with a detailed section regarding fish. We calculated the correlations between Hg and Se in the biological samples and estimated the association between Hg concentrations and fish consumption. RESULTS: in general, Hg levels in hair and milk were positively associated with the consumption of fish from the lagoon of Grado and Marano. However, they were low in comparison with those of other fish-eating populations and below theWHO alert limits, likely because of the small consumption of fish among pregnant women, estimated from the FFQ. The concentration of Se in milk was also smaller than that reported in other international studies. CONCLUSION: in Friuli Venezia Giulia, fetal and perinatal Hg exposure is low. The children of the cohort will be followed- up at school age to measure possible neurodevelopmental effects of such low exposures to Hg.

Genetic basis of neural tube defects.

Neural tube defects (NTDs) represent a common group of severe congenital malformations of the central nervous system. They result from failure of neural tube closure during early embryonic life. Their etiology is complex, involving environmental and genetic factors that interact to modulate the incidence and severity of the developing phenotype. Despite a long history of etiologic studies, the molecular and cellular pathogenic mechanisms underlining NTDs remain poorly understood. The major epidemiologic finding in NTDs is the protective effect of perinatal folic acid supplementation that reduces their risk by 60%-70%. Genetic studies in NTDs have focused mainly on folate-related genes and identified a few significant associations between variants in these genes and an increased risk for NTDs. The candidate gene approach investigating genes involved in neurulation and inferred from animal models has faced limited success in identifying major causative genes predisposing to NTDs. However, we are witnessing a rapid and impressive progress in understanding the genetic basis of NTDs, based mainly on the development of whole genome innovative technologies and the powerful tool of animal models.

Early development, pattern, and reorganization of the planula nervous system in Aurelia (Cnidaria, Scyphozoa).

We examined the development of the nervous system in Aurelia (Cnidaria, Scyphozoa) from the early planula to the polyp stage using confocal and transmission electron microscopy. Fluorescently labeled anti-FMRFamide, antitaurine, and antityrosinated tubulin antibodies were used to visualize the nervous system. The first detectable FMRFamide-like immunoreactivity occurs in a narrow circumferential belt toward the anterior/aboral end of the ectoderm in the early planula. As the planula matures, the FMRFamide-immunoreactive cells send horizontal processes (i.e., neurites) basally along the longitudinal axis. Neurites extend both anteriorly/aborally and posteriorly/orally, but the preference is for anterior neurite extension, and neurites converge to form a plexus at the aboral/anterior end at the base of the ectoderm. In the mature planula, a subset of cells in the apical organ at the anterior/aboral pole begins to show FMRFamide-like and taurine-like immunoreactivity, suggesting a sensory function of the apical organ. During metamorphosis, FMRFamide-like immunoreactivity diminishes in the ectoderm but begins to occur in the degenerating primary endoderm, indicating that degenerating FMRFamide-immunoreactive neurons are taken up by the primary endoderm. FMRFamide-like expression reappears in the ectoderm of the oral disc and the tentacle anlagen of the growing polyp, indicating metamorphosis-associated restructuring of the nervous system. These observations are discussed in the context of metazoan nervous system evolution.

[Perinatal management and neurological outcome of newborns hospitalized with Rhesus hemolytic disease]. / Prise en charge périnatale et devenir neurologique à moyen terme des nouveau-nés hospitalisés pour maladie hémolytique par immunisation anti-D.

OBJECTIVES: To evaluate perinatal management and neurological outcome in a group of infants born with Rhesus fetomaternal allo-immunization. PATIENTS AND METHODS: Between 1 January and 31 December 2005, all newborns admitted to neonatal unit of Rouen tertiary centre for Rhesus hemolytic disease were included in a retrospective study and divided in two groups. The newborns who were treated with intrauterine transfusion are in the group 1 and those who needed only postnatal treatment in the group 2. In each case, were considered antenatal management (ultrasonographic data, middle cerebral artery peak systolic velocity, intrauterine transfusion), postnatal treatment (phototherapy, exchange transfusion, transfusion requirements) and neurological outcome. RESULTS: Among 42 cases of Rhesus allo-immunization observed in six years, 28 newborns (67%) were admitted for neonatal cares. No case of fetal hydrops was noted. But 16/28 (57%) were preterm with a median term of 35 weeks gestation (32-36 weeks). In group 1 of six infants who had received intrauterine transfusion (IUT), only one (17%) needed postnatal exchange transfusion, and all six received one to three blood transfusions after their birth. In group 2 of 22 infants who did not receive IUT, 6/22 (27%) needed postnatal exchange and 18/22 (82%) of them received one to four blood transfusions. Phototherapy duration and albumin requirements were similar in both groups. Three deaths occurred, one due to necrotizing enterocolitis and the other two later on due to sudden infant death and fulminant meningococcemia. Neurological outcome of the remaining 25 children was normal. DISCUSSION AND CONCLUSION: Rhesus alloimmunization remain a situation at risk. Neonatal clinical presentation is less severe than previously described due to improvement in antenatal management. Infants required less postnatal exchange transfusion when they received intrauterine transfusion but more frequent blood transfusions.

The Yin and Yang of YY1 in the nervous system.

The transcription factor Yin Yang 1 (YY1) is a multifunctional protein that can activate or repress gene expression depending on the cellular context. YY1 is ubiquitously expressed and highly conserved between species. However, its role varies in diverse cell types and includes proliferation, differentiation, and apoptosis. This review will focus on the function of YY1 in the nervous system including its role in neural development, neuronal function, developmental myelination, and neurological disease. The multiple functions of YY1 in distinct cell types are reviewed and the possible mechanisms underlying the cell specificity for these functions are discussed.

The beginning of individual human personhood.

Even for persons who hold to the ethical acceptance of abortion practices in general, questions of detail often arise. If you assume the distinction between the physical human organism alone and the person that is associated with that organism, then you must face the question of whether it is permissible to abort a fetus if the corresponding person has come into being. We take the position that the abortion of a fetus that has achieved this level of development should be declared unethical except in special circumstances. Our purpose here is to identify the point in the development of the fetus that serves as the marker for this level.

Fetal onset of general movements.

Perinatal qualitative assessment of general movements (GMs) is a tool to evaluate the integrity of the young nervous system. The aim of this investigation was to study the emergence of GMs. Fetal onset of GMs was studied sonographically in 18 fetuses during the first trimester of uncomplicated in vitro fertilization (IVF) pregnancies in weekly assessments. The earliest motility consisting of small and simple sideways bending (SB) of head and/or rump starts at 7 wk, lasting about 1 s. Between 7 and 8.5 wk, motility differentiates further into movements in which also one or two arms or legs become active; movements are still slow, small, and in one direction, but the duration increases to a few seconds. The transition into GMs at 9-10 wk is characterized by variation in participating body parts and amplitude, speed, and direction during longer periods of time. Between 9 and 13 wk, simple and stereotyped SBs and GMs may coexist. At 9 wk, the incidence of SBs decreases (p = 0.01) and that of GMs increases (p = 0.006). The data suggest that initial simple fetal motility is generated by spinal and brainstem circuitries, and the emergence of complex and variable GMs denotes the onset of supraspinal modulation of this spinal and brainstem activity.

PX-RICS, a novel splicing variant of RICS, is a main isoform expressed during neural development.

In our previous study, we identified RICS, a novel beta-catenin-interacting protein with the GAP activity toward Cdc42 and Rac1, and found that RICS plays an important role in the regulation of neural functions, including postsynaptic NMDA signaling and neurite outgrowth. Here we report the characterization of an N-terminal splicing variant of RICS, termed PX-RICS, which has additional phox homology (PX) and src homology 3 (SH3) domains in its N-terminal region. The PX domain of PX-RICS interacted specifically with phosphatidylinositol 3-phosphate [PtdIns(3)P], PtdIns(4)P and PtdIns(5)P. Consistent with this binding affinity, PX-RICS was found to be localized at the endoplasmic reticulum (ER), Golgi and endosomes. We also found that wild-type PX-RICS possessed much lower GAP activity than RICS, whereas a mutant form of PX-RICS whose PX domain lacks the binding ability to phosphoinositides (PIs) exhibited the GAP activity comparable to that of RICS. However, PX-RICS and RICS exhibited similar inhibitory effects on neurite elongation of Neuro-2a cells. Furthermore, we demonstrate that PX-RICS is a main isoform expressed during neural development. Our results suggest that PX-RICS is involved in early brain development including extension of axons and dendrites, and postnatal remodeling and fine-tuning of neural circuits.

Ethanol regulates angiogenic cytokines during neural development: evidence from an in vitro model of mitogen-withdrawal-induced cerebral cortical neuroepithelial differentiation.

BACKGROUND: Heavy alcohol consumption during pregnancy can cause significant mental retardation and brain damage. We recently showed that ethanol depletes reserve cerebral cortical stem cell capacity. Moreover, proliferating neuroepithelial cells exposed to ethanol were resistant to subsequent retinoic acid-induced differentiation. Emerging evidence suggests that cytokines play a crucial growth-promoting role in the developing neural tube. METHODS: We cultured murine cortical neurosphere cultures in control or ethanol-supplemented mitogenic medium, to mimic alcohol exposure during the period of neuroepithelial proliferation. Cultures were then treated with a step-wise mitogen-withdrawal, integrin-activation model to mimic subsequent phases of neuronal migration and early differentiation. We examined the impact of alcohol exposure during neurogenesis on the secretion of inflammatory and growth-promoting cytokines. RESULTS: Cortical neurosphere cultures exhibit increasingly complex differentiation phenotypes in response to step-wise mitogen-withdrawal and laminin exposure. Some inflammation-modulating cytokines were secreted independent of differentiation state. However, chemotactic cytokines were specifically secreted at high levels, as a function of differentiation stage. monocyte chemotactic protein-1, vascular endothelial growth factor-A, and interleukin (IL)-10 were coordinately decreased during differentiation compared with neuroepithelial proliferation, while granulocyte macrophage-colony stimulating factor (GM-CSF) was induced during differentiation, compared with the neuroepithelial proliferation period. Ethanol exposure during the period of neuroepithelial proliferation prevented the early differentiation-induced increase in GM-CSF while inducing differentiation-associated increase in IL-12 secretion. CONCLUSION: Embryonic cerebral cortical neuroepithelial-derived precursors secrete high levels of several angiogenic and neural-growth-promoting cytokines as they differentiate into neurons. Our data collectively suggest that ethanol exposure during the period of neuroepithelial proliferation significantly disrupts cytokine signals that are required for the support of emerging neurovascular networks, and the maintenance of neural stem cell beds.

Xenopus Zic4: conservation and diversification of expression profiles and protein function among the Xenopus Zic family.

We compared the expression and function of Xenopus Zic4 with those of the other four Xenopus laevis Zic family members (Zic1, Zic2, Zic3, and Zic5). Zic4 expression was detected mainly in the neural plate border, dorsal neural tube, and somites, and was similar to that of Zic1, which is adjacent to Zic4 on the same chromosome. Injection of wild-type or mutant Zic4 RNA caused the induction of neural crest marker gene expression, hyperplastic neural tissue, and ectopic pigment cell formation, indicating that Zic4 can induce neural and neural crest tissue, as can other Xenopus Zic genes. Deletion analysis showed that the zinc-finger domain is critical for many Zic4 functions, but the C-terminal region is differently involved in induction of two neural crest markers, Slug and Sox10. The protein function as determined by the animal cap explant assay was similar to that of Zic5, but different from those of Zic1, Zic2, and Zic3, suggesting that Xenopus Zic genes can be divided into two groups based on function. These results indicate that the five Xenopus Zic genes cooperatively regulate both neural and neural crest development, despite significantly diverged expression profiles and functions.

The effects of high dose progesterone on neural tube development in early chick embryos.

BACKGROUND: Although folic acid deficiency is known to be one of the factors in the development of spina bifida and other neural tube defects (NTD) the exact pathophysiology still remains unclear. Progesterone is an endogenous hormone which increases significantly during pregnancy. AIMS: We aimed to study the possible negative effects of high dose progesterone on neural tube development in early chick embryos. In order to test our hypothesis, early chick embryos were exposed to physiological saline, normal and high doses of progesterone. SETTINGS AND DESIGN: 160 fertile, specific pathogen free white leghorn eggs (Gallus gallus), all at stage eight of development were divided into four equal groups. MATERIALS AND METHODS: The first group was incubated without any operation. The second group was injected with physiological saline. The third and fourth groups were injected with two and twenty times more than physiologic doses of progesterone respectively. After 48 hours of incubation, all embryos were analyzed for the presence of NTDs under light microscopy. STATISTICAL ANALYSIS USED: None. RESULTS: At 48 hours of incubation, 84% (135/160) of the embryos passed characteristics of Stage 12 development and were included to the study. None of the eggs in the first three groups showed NTDs, whereas 81.8% (27/33) of the eggs in the fourth group showed NTDs. CONCLUSIONS: Our study showed that progesterone at levels twenty times more than its physiologic level might cause NTDs. Further studies are needed to explain the mechanisms of this teratogenic effect.

Members of the Plag gene family are expressed in complementary and overlapping regions in the developing murine nervous system.

In the developing nervous system, cell fate specification and proliferation are tightly coupled events, ensuring the coordinated generation of the appropriate numbers and correct types of neuronal and glial cells. While it has become clear that tumor suppressor genes and oncogenes are key regulators of cell division in tumor cells, their role in normal cellular and developmental processes is less well understood. Here we present a comparative analysis of the expression profiles of the three members of the pleiomorphic adenoma gene (Plag) family, which encode zinc finger transcription factors previously characterized as tumor suppressors (Zac1) or oncogenes (Plag1, Plag-l2). We focused our analysis on the developing nervous system of mouse where we found that the Plag genes were expressed in both unique and overlapping patterns in the central and peripheral nervous systems, and in olfactory and neuroendocrine lineages. Based on their patterns of expression, we suggest that members of the Plag gene family might control cell fate and proliferation decisions in the developing nervous system and propose that deciphering these functions will help to explain why their inappropriate inactivation/activation leads to tumor formation.