Abnormal Development Of Central Nervous System Research Articles

The Polycomb group gene rnf2 is essential for central and enteric neural system development in zebrafish.

The development of central nervous system (CNS) and enteric nervous system (ENS) is under precise and strict control in vertebrates. Whether and how the Polycomb repressive complex 1 (PRC1) is involved in it remain unclear. To investigate the role of PRC1 in the nervous system development, using CRISPR/Cas9 technology, we have generated mutant zebrafish lines for the rnf2 gene which encodes Ring1b, the enzymatic component of the PRC1 complex. We show that rnf2 loss of function leads to abnormal migration and differentiation of neural crest and neural precursor cells. rnf2 mutant embryos exhibit aganglionosis, in which the hindgut is devoid of neurons. In particular, the formation of 5-HT serotonin neurons and myelinating glial cells is defective. Furthermore, ectopic expression of ENS marker genes is observed in forebrain of rnf2 mutant embryos. These findings suggest that the rnf2 gene plays an important role in the migration and differentiation of neural precursor cells, and its absence leads to abnormal development of ENS and CNS in zebrafish.

In utero infection of Zika virus leads to abnormal central nervous system development in mice

The World Health Organization has declared ZIKA virus (ZIKV) a global public health emergency, prompted by the association of ZIKV infections with severe brain abnormalities in the human fetus. ZIKV preferentially targets human neuronal precursor cells (NPCs) in both monolayer and cortical brain organoid culture systems and stunts their growth. Although ZIKV is well recognized to cause microcephaly, there is no systematic analysis to demonstrate the effect of ZIKV on central nervous system (CNS) development, including brain malformations and spinal cord dysfunction. Here, we conducted a longitudinal analysis to show that a novel mouse model (infected in utero and monitored after birth until adulthood) recapitulates the effects of ZIKV infection affecting neural stem cells fate and leads to a thinner cortex and a smaller brain. Furthermore, we demonstrate the effect of ZIKV on spinal cord function. Specifically, we found significant reductions in neuron numbers in the anterior horn of grey matter of the spinal cord and muscle dystrophy with a significant decrease in forepaw grip strength in the ZIKV group. Thus, the established mouse model of ZIKV infection leading to abnormal CNS development will help to further advance our understanding of the disease pathogenesis.

DCCmutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome

The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).

Maternal Iron Deficiency Heightens Fetal Susceptibility to Metabolic Syndrome in Adulthood

Iron is involved in the functional conformation of hemoglobin; it facilitates hemoglobin binding to oxygen. Iron also has a critical role in erythropoiesis. When erythroblasts proliferate and differentiate, they require large amounts of iron for hemoglobin synthesis. The heme moiety of erythroblasts requires iron for synthesis, and it regulates globin production. Thus, iron deficiency (ID) causes anemia, which is associated with many diseases. Because ID in the adult has a detrimental influence on erythrocyte function, maternal ID affects fetal development; thereafter, many physiological functions may be altered in the offspring. In rats fed a low-iron diet, although maternal ID did not cause severe anemia in the dam, brain development in the offspring was profoundly impaired; their offspring showed an increased auditory brainstem response time later in life, which suggested an impairment in brain development (1). Thus, subclinical anemia in the mother during early pregnancy may be a risk factor for abnormal central nervous system development in the fetus. The authors also showed that there was a time window for the susceptibility of brain development to ID (1). The fetal stage was thought to be the most vulnerable stage during development (2). The bottom line was that, when a fetus had experienced maternal ID, health problems become manifest in adulthood, despite adequate adult nutrition. Although animals are resistant to diet-induced obesity under normal circumstances, feeding with a high-fat diet (HFD) induces obesity in many experimental animals. Therefore, HFD is widely used as a model for the Western diet, which is thought to be an important risk factor for obesity. In turn, obesity increases the risk for metabolic syndrome, which includes cardiovascular disease. Therefore, the relationship between obesity and the Western diet has a profound impact on public health. Because the time range of highest vulnerability in brain development occurs in the fetal stage, one might expect that some abnormal development of the brain at that time could affect the adult’s susceptibility to obesity (3). In fact, the thrifty phenotype hypothesis proposed that poor nutrition in early life causes subsequent development of the metabolic syndrome in adults (4). It is now recognized that intrauterine undernutrition or excessive maternal feeding, including a HFD, affects the developmental programming of the offspring, and changes can be manifest in adulthood (5). Thus, the risk for adult health problems, particularly metabolic syndrome, can be markedly influenced by fetal and prenatal environmental exposures. Interestingly, many abnormal feeding behaviors are manifest only with the HFD. For example, heterozygote carriers of the proopiomelanocortin gene mutation are predisposed to obesity. Under normal feeding conditions, these mice maintained a normal weight; however, when fed a HFD, these mice became significantly obese (6). This also occurred with pharmacological receptor manipulations (7). Similar responses were observed in neuropeptide Y knockout mice. When fed normal chow, they look healthy, but when fed a HFD, they become obese (8). These are only a few examples, but they showed that the HFD is useful for revealing diseases. In this issue of Endocrinology, Bourque et al. (9) reported that mouse offspring exposed to maternal ID during the gestational period developed a susceptibility to HFD-induced obesity; in addition, they developed glucose intolerance and increases in blood pressure. These symptoms are indicative of metabolic syndrome. Dams fed a

Feasibility study on repair for cranial defect of immaturity

To evaluate use of a titanium mesh to fill cranial defects in growing animals, as a model for juvenile humans. Thirty two-month-old Seghers pigs were evenly assigned to one of three groups: controls, a defect group (unrepaired 5 x 5 cm lesion), and a repair group (repaired 5 x 5 cm lesions). Histological evaluations and morphological measurements were conducted to compare the groups. Two pigs in the defect group died. New bone formation was evident in the cranial lesions of pigs in the defect and repair groups. There were no differences in histological observations (p = 0.081), brain weight (p = 0.063), or indexed brain circumference measurements (p = 0.066) between the groups. Closure of cranial defects with a titanium mesh did not limit growth of the cranium or cause abnormal central nervous system development. While there was new bone growth in the cranial defects, the bone was not sufficiently strong to withstand external trauma.

3D and 4D sonography and magnetic resonance in the assessment of normal and abnormal CNS development: alternative or complementary

Advanced transvaginal neurosonography has revealed normal and abnormal intracranial morphology. Transvaginal three-dimensional (3D) sonography demonstrates bony structure, multiplanar analysis of inside detailed morphology, tomographic ultrasound imaging in any cutting sections, 3D sonoangiography and volume calculation of ventricles and/or intracranial lesions. Longitudinal assessment of normal and abnormal central nervous system (CNS) development is done by serial scanning. However, the transvaginal high-frequency approach has several limitations due to lack of penetration and cranial bone ossification with advanced gestational age. Magnetic resonance neuroimaging enabled observation of the whole intracranial cavity, brainstem and cortical gyral/sulcal development. On the other hand, neuro-sonography has advantages in detecting intracranial calcification, vascular abnormalities, intratumoral vascularity and bone dysplasia. Moreover, 3D ultrasound demonstrates extra CNS abnormalities, strongly associated with CNS abnormalities. Any less-invasive modalities can be used for a CNS anomaly screening scan and ultrasound is no doubt the first choice. Once CNS abnormality is suspected, it is suggested to use the different technologies according to what is looked for in each abnormal CNS case. Of course, MR and 3D ultrasound imaging should be complementary as well as alternative.

Zinc: The brain's dark horse

Zinc is a life-sustaining trace element, serving structural, catalytic, and regulatory roles in cellular biology. It is required for normal mammalian brain development and physiology, such that deficiency or excess of zinc has been shown to contribute to alterations in behavior, abnormal central nervous system development, and neurological disease. In this light, it is not surprising that zinc ions have now been shown to play a role in the neuromodulation of synaptic transmission as well as in cortical plasticity. Zinc is stored in specific synaptic vesicles by a class of glutamatergic or "gluzinergic" neurons and is released in an activity-dependent manner. Because gluzinergic neurons are found almost exclusively in the cerebral cortex and limbic structures, zinc may be critical for normal cognitive and emotional functioning. Conversely, direct evidence shows that zinc might be a relatively potent neurotoxin. Neuronal injury secondary to in vivo zinc mobilization and release occurs in several neurological disorders such as Alzheimer's disease and amyotrophic lateral sclerosis, in addition to epilepsy and ischemia. Thus, zinc homeostasis is integral to normal central nervous system functioning, and in fact its role may be underappreciated. This article provides an overview of zinc neurobiology and reviews the experimental evidence that implicates zinc signals in the pathophysiology of neuropsychiatric diseases. A greater understanding of zinc's role in the central nervous system may therefore allow for the development of therapeutic approaches where aberrant metal homeostasis is implicated in disease pathogenesis.

Prenatal Head Growth and White Matter Injury in Hypoplastic Left Heart Syndrome

Children with hypoplastic left heart syndrome (HLHS) have an increased prevalence of central nervous system (CNS) abnormalities. The extent to which this problem is due to CNS maldevelopment, prenatal ischemia, postnatal chronic cyanosis and/or multiple exposures to cardiopulmonary bypass is unknown. To better understand the etiology of CNS abnormalities in HLHS, we evaluated 68 neonates with HLHS; in 28 cases, both fetal ultrasound and echocardiogram data were available to assess head size, head growth and aortic valve anatomy (atresia or stenosis). In addition, we evaluated neuropathology in 11 electively aborted HLHS fetuses. The mean head circumference percentile in HLHS neonates was significantly smaller than HLHS fetuses (22 +/- 2% versus 40 +/- 4%, p < 0.001). A significant decrease in head growth, defined as a 50% reduction in head circumference percentile, was observed in half (14/28) of HLHS fetuses and nearly a quarter (6/28) were already growth restricted (<or=10%) at the time of initial evaluation. Brains from HLHS fetuses demonstrated chronic diffuse white matter injury of varying severity. These patterns of prenatal head growth and brain histopathology identify a spectrum of abnormal CNS development and/or injury in HLHS fetuses.

Disruption of Contactin 4 ( CNTN4) Results in Developmental Delay and Other Features of 3p Deletion Syndrome

3p deletion syndrome is a rare contiguous-gene disorder involving the loss of the telomeric portion of the short arm of chromosome 3 and characterized by developmental delay, growth retardation, and dysmorphic features. All reported cases have involved, at a minimum, the deletion of chromosome 3 telomeric to the band 3p25.3. Despite the presence of several genes in this region that are involved in neural development, a causative relationship between a particular transcript and the observed clinical manifestations has remained elusive. We have identified a child with characteristic physical features of 3p deletion syndrome and both verbal and nonverbal developmental delay who carries a de novo balanced translocation involving chromosomes 3 and 10. Fine mapping of this rearrangement demonstrates that the translocation breakpoint on chromosome 3 falls within the recently identified minimal candidate region for 3p deletion syndrome and disrupts the Contactin 4 (CNTN4) mRNA transcript at 3p26.2–3p26.3. This transcript (also known as BIG-2) is a member of the immunoglobulin super family of neuronal cell adhesion molecules involved in axon growth, guidance, and fasciculation in the central nervous system (CNS). Our results demonstrate the association of CNTN4 disruption with the 3p deletion syndrome phenotype and strongly suggest a causal relationship. These findings point to an important role for CNTN4 in normal and abnormal CNS development.

Impact of intrauterine growth restriction and glucocorticoids on brain development: Insights using advanced magnetic resonance imaging

There are now a number of evidences showing that the developing organism adapts to the environment it finds itself. Short- and long-term adjustments, referred as “programming”, take place and will initially induce intrauterine growth retardation but will also have consequences that will appear later in life. The use of magnetic resonance imaging (MRI) techniques in IUGR babies has delineated changes in the central nervous system (CNS) development that correlate with altered neurodevelopment and could be implicated in the development of neuropsychiatric disorders in adult life. Similarly, the use of corticosteroid treatment in preterm infants has also been implicated in abnormal CNS development. In this review, we will focus on the modifications of CNS development that occur after exposition to adverse environment such as undernutrition or corticosteroid treatment that can now be studied in vivo with advanced MRI technology.

Temporal Soft Tissue Glioneuronal Heterotopia in a Child with a Seizure Disorder: Case Report and Review of the Literature

Tissue and cellular elements generally attributed to the central nervous system (CNS) are infrequently found in areas outside the CNS proper. Most of these lesions contain predominantly glial tissue. In rare instances, heterotopic CNS tissue is found in the scalp, many associated with an intracranial connection and overlying skin and hair anomalies. In follow-up of these patients, development is normal. We present a case of a temporal scalp mass in a 19-month-old girl with a seizure disorder beginning at about age 1 year. At the time of excision, the mass was not associated with intracranial connection or overlying cutaneous abnormalities and demonstrated abundant neuronal and glial elements with features of dysplastic CNS tissue. We speculate that, in certain circumstances, aberrantly localized CNS tissue may be related to abnormal CNS development.

Disruption of Contactin 4 ( CNTN4) Results in Developmental Delay and Other Features of 3p Deletion Syndrome

3p deletion syndrome is a rare contiguous-gene disorder involving the loss of the telomeric portion of the short arm of chromosome 3 and characterized by developmental delay, growth retardation, and dysmorphic features. All reported cases have involved, at a minimum, the deletion of chromosome 3 telomeric to the band 3p25.3. Despite the presence of several genes in this region that are involved in neural development, a causative relationship between a particular transcript and the observed clinical manifestations has remained elusive. We have identified a child with characteristic physical features of 3p deletion syndrome and both verbal and nonverbal developmental delay who carries a de novo balanced translocation involving chromosomes 3 and 10. Fine mapping of this rearrangement demonstrates that the translocation breakpoint on chromosome 3 falls within the recently identified minimal candidate region for 3p deletion syndrome and disrupts the Contactin 4 (CNTN4) mRNA transcript at 3p26.2-3p26.3. This transcript (also known as BIG-2) is a member of the immunoglobulin super family of neuronal cell adhesion molecules involved in axon growth, guidance, and fasciculation in the central nervous system (CNS). Our results demonstrate the association of CNTN4 disruption with the 3p deletion syndrome phenotype and strongly suggest a causal relationship. These findings point to an important role for CNTN4 in normal and abnormal CNS development.

Neurodevelopmental follow-up of children of women infected with varicella during pregnancy: a prospective study.

The fetal varicella syndrome is associated with abnormal central nervous system development, which in many cases is associated with mental retardation. However, the incidence of neurobehavioral deficits in asymptomatic structurally normal children whose mothers had clinically diagnosed varicella-zoster virus infection is unknown. Neurobehavioral outcome was evaluated in 84 children born to women infected with varicella during pregnancy and 40 children born to women who were not infected with varicella during pregnancy. Children were 3 to 15 years of age at the time of testing. Clinical features of the fetal varicella syndrome were present in only 1 of the 84 children in the varicella group. These sample sizes provide statistical power of 0.80 (alpha = 0.05) to detect group differences of 0.54 sd (the equivalent of 8.1 IQ points). No differences were found in the test performance of the two groups. In addition, within the varicella sample, no meaningful differences were found relative to infection-related hyperthermia or the timing of infection. As a group, the children born to women infected with varicella-zoster virus during pregnancy and who do not have structural features characteristic of the fetal varicella syndrome are not neurodevelopmentally different from unexposed, uninfected control children.

Ophthalmic manifestations of neonatal onset multisystem inflammatory disease

PURPOSE: To report the ophthalmic manifestations of neonatal onset multisystem inflammatory disease, a recently recognized, rare systemic disorder characterized by the triad of arthropathy, rash, and abnormal central nervous system development. METHOD: Case report. RESULTS: A 2-year-old female with neonatal onset multisystem inflammatory disease presented with visual acuity of fix and follow with each eye, bilateral optic nerve head pallor and gliosis, as well as marked sheathing of the peripapillary vessels. No vitreous inflammation or macular edema was found. Visual acuity was stable from the neonatal period through the 3 months of follow-up after the changes involving the optic nerve heads and peripapillary vessels were observed (a total of 33 months). CONCLUSIONS: This report provides a description of the ocular manifestations of neonatal onset multisystem inflammatory disease and supports earlier suggestions that swelling of the optic nerve heads can occur. In this case, optic nerve head pallor may have been a sequela of such swelling. The pathogenesis of neonatal onset multisystem inflammatory disease is unknown.

The effects of disulfiram on the experimental C3H mouse embryo.

Disulfiram, in 1 mg and 10 mg oral doses, was given to inbred C3H mice prior to and for the duration of pregnancy. The effects on the fetus have been assessed at 18 days gestation by means of fetal and placental weights, number of resorptions, skeletal preparations and Wilson's sections. Disulfiram dissolved in diethyl ether was administered to 8- and 9-day embryos in vitro in concentrations of 0.1, 10 and 100 micrograms ml-1 of culture medium, and the effects of ether alone and ether plus disulfiram assessed by evaluation of morphological development over a 28-h period, and inhibition of DNA synthesis using tritiated thymidine labelling over a 4-h period. Disulfiram (1 mg) in vivo caused no adverse effects on the fetus, but disulfiram (10 mg) was toxic, in that it caused a significant increase in early resorptions. Disulfiram in vitro, in the 10 and 100 micrograms ml-1 concentrations, proved to be very toxic to the embryos, affecting both morphological development and DNA synthesis in 9-day embryos and morphological development in 8-day embryos. DNA synthesis was only inhibited at the 100 micrograms ml-1 concentration in 8-day embryos. The 0.1 micrograms ml-1 concentration of disulfiram caused abnormal central nervous system development in 8-day embryos, but was otherwise non-toxic to 8- and 9-day embryos. Apart from a reduction in somite counts, ether in concentrations of 0.285 mg ml-1 and 2.85 mg ml-1 caused no adverse effects on morphological development in 8- or 9-day embryos. DNA synthesis was inhibited by ether in a concentration of 2.85 mg ml-1 in 9-day embryos.