scholarly journals PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1782
Author(s):  
Sahar I. Da’as ◽  
Waleed Aamer ◽  
Waseem Hasan ◽  
Aljazi Al-Maraghi ◽  
Alya Al-Kurbi ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Early Development ◽  
Motor Neurons ◽  
System Development ◽  
Tube Formation ◽  
Nervous System Development ◽  
Global Developmental Delay ◽  
Recessive Mutations ◽  
Fetal Movements ◽  
Neuromuscular Responses

Recessive mutations in Post-GPI attachment to proteins 3 (PGAP3) cause the rare neurological disorder hyperphosphatasia with mental retardation syndrome 4 type (HPMRS4). Here, we report a novel homozygous nonsense mutation in PGAP3 (c.265C>T-p.Gln89*), in a 3-year-old boy with unique novel clinical features. These include decreased intrauterine fetal movements, dysgenesis of the corpus callosum, olfactory bulb agenesis, dysmorphic features, cleft palate, left ear constriction, global developmental delay, and hypotonia. The zebrafish functional modeling of PGAP3 loss resulted in HPMRS4-like features, including structural brain abnormalities, dysmorphic cranial and facial features, hypotonia, and seizure-like behavior. Remarkably, morphants displayed defective neural tube formation during the early stages of nervous system development, affecting brain morphogenesis. The significant aberrant midbrain and hindbrain formation demonstrated by separation of the left and right tectal ventricles, defects in the cerebellar corpus, and caudal hindbrain formation disrupted oligodendrocytes expression leading to shorter motor neurons axons. Assessment of zebrafish neuromuscular responses revealed epileptic-like movements at early development, followed by seizure-like behavior, loss of touch response, and hypotonia, mimicking the clinical phenotype human patients. Altogether, we report a novel pathogenic PGAP3 variant associated with unique phenotypic hallmarks, which may be related to the gene’s novel role in brain morphogenesis and neuronal wiring.

scholarly journals Molecular and Comparative Genetics of Mental Retardation

Genetics ◽  
2004 ◽  
Vol 166 (2) ◽  
pp. 835-881 ◽  
Author(s):  
Jennifer K Inlow ◽  
Linda L Restifo
Keyword(s):  
Mental Retardation ◽  
Homo Sapiens ◽  
System Development ◽  
Laboratory Data ◽  
Fruit Fly ◽  
Mendelian Inheritance ◽  
Nervous System Development ◽  
Skewed Distribution ◽  
Therapeutic Drug ◽  
Cellular Mechanisms

Abstract Affecting 1-3% of the population, mental retardation (MR) poses significant challenges for clinicians and scientists. Understanding the biology of MR is complicated by the extraordinary heterogeneity of genetic MR disorders. Detailed analyses of >1000 Online Mendelian Inheritance in Man (OMIM) database entries and literature searches through September 2003 revealed 282 molecularly identified MR genes. We estimate that hundreds more MR genes remain to be identified. A novel test, in which we distributed unmapped MR disorders proportionately across the autosomes, failed to eliminate the well-known X-chromosome overrepresentation of MR genes and candidate genes. This evidence argues against ascertainment bias as the main cause of the skewed distribution. On the basis of a synthesis of clinical and laboratory data, we developed a biological functions classification scheme for MR genes. Metabolic pathways, signaling pathways, and transcription are the most common functions, but numerous other aspects of neuronal and glial biology are controlled by MR genes as well. Using protein sequence and domain-organization comparisons, we found a striking conservation of MR genes and genetic pathways across the ∼700 million years that separate Homo sapiens and Drosophila melanogaster. Eighty-seven percent have one or more fruit fly homologs and 76% have at least one candidate functional ortholog. We propose that D. melanogaster can be used in a systematic manner to study MR and possibly to develop bioassays for therapeutic drug discovery. We selected 42 Drosophila orthologs as most likely to reveal molecular and cellular mechanisms of nervous system development or plasticity relevant to MR.

scholarly journals Molecular and Functional Mapping of the Piebald Deletion Complex on Mouse Chromosome 14

Genetics ◽  
2001 ◽  
Vol 157 (2) ◽  
pp. 803-815
Author(s):  
Jeffrey J Roix ◽  
Aaron Hagge-Greenberg ◽  
Dennis M Bissonnette ◽  
Sandra Rodick ◽  
Liane B Russell ◽  
...  
Keyword(s):  
Mouse Chromosome ◽  
System Development ◽  
Genomic Region ◽  
Nervous System Development ◽  
Chromosome 14 ◽  
Developmental Defects ◽  
Oak Ridge ◽  
Recessive Mutations ◽  
Large Deletions ◽  
Critical Regions

Abstract The piebald deletion complex is a set of overlapping chromosomal deficiencies surrounding the endothelin receptor B locus collected during the Oak Ridge specific-locus-test mutagenesis screen. These chromosomal deletions represent an important resource for genetic studies to dissect the functional content of a genomic region, and several developmental defects have been associated with mice homozygous for distinct piebald deletion alleles. We have used molecular markers to order the breakpoints for 20 deletion alleles that span a 15.7–18-cM region of distal mouse chromosome 14. Large deletions covering as much as 11 cM have been identified that will be useful for regionally directed mutagenesis screens to reveal recessive mutations that disrupt development. Deletions identified as having breakpoints positioned within previously described critical regions have been used in complementation studies to further define the functional intervals associated with the developmental defects. This has focused our efforts to isolate genes required for newborn respiration and survival, skeletal patterning and morphogenesis, and central nervous system development.

scholarly journals Differing strategies used by motor neurons and glia to achieve robust development of an adult neuropil in Drosophila

2017 ◽  
Author(s):  
Jonathan Enriquez ◽  
Laura Quintana Rio ◽  
Richard Blazeski ◽  
Carol Mason ◽  
Richard S. Mann
Keyword(s):  
Stem Cells ◽  
Nervous System ◽  
Birth Order ◽  
Motor Neurons ◽  
Neural Circuits ◽  
System Development ◽  
Cell Types ◽  
Nervous System Development ◽  
Factor Code ◽  
Individual Motor

SummaryIn both vertebrates and invertebrates, neurons and glia are generated in a stereotyped order from dedicated progenitors called neural stem cells, but the purpose of invariant lineages is not understood. Here we show that three of the stem cells that produce leg motor neurons in Drosophila also generate a specialized subset of glia, the neuropil glia, which wrap and send processes into the neuropil where motor neuron dendrites arborize. The development of the neuropil glia and leg motor neurons is highly coordinated. However, although individual motor neurons have a stereotyped birth order and transcription factor code, both the number and individual morphologies of the glia born from these lineages are highly plastic, even though the final structure they contribute to is highly stereotyped. We suggest that the shared lineages of these two cell types facilitates the assembly of complex neural circuits, and that the two different birth order strategies – hardwired for motor neurons and flexible for glia – are important for robust nervous system development and homeostasis.

Integrin alpha 6 expression is required for early nervous system development in Xenopus laevis

Development ◽  
1996 ◽  
Vol 122 (8) ◽  
pp. 2539-2554 ◽  
Author(s):  
T.E. Lallier ◽  
C.A. Whittaker ◽  
D.W. DeSimone
Keyword(s):  
Nervous System ◽  
Early Development ◽  
System Development ◽  
Cranial Nerves ◽  
Nervous System Development ◽  
Neural Plate ◽  
Pronephric Duct ◽  
Axial Defects ◽  
Integrin Alpha 6

The integrin alpha 6 subunit pairs with both the beta 1 and beta 4 subunits to form a subfamily of laminin receptors. Here we report the cDNA cloning and primary sequence for the Xenopus homologue of the mammalian integrin alpha 6 subunit. We present data demonstrating the spatial and temporal expression of alpha 6 mRNA and protein during early development. Initially, alpha 6 transcripts are expressed in the dorsal ectoderm and future neural plate at the end of gastrulation. Later in development, alpha 6 mRNAs are expressed in a variety of neural derivatives, including the developing sensory placodes (otic and olfactory) and commissural neurons within the neural tube. Integrin alpha 6 is also expressed in the elongating pronephric duct as well as a subset of the rhombencephalic neural crest, which will form the Schwann cells lining several cranial nerves (VII, VIII and X). In vivo expression of an alpha 6 antisense transcript in the animal hemisphere leads to a reduction in alpha 6 protein expression, a loss of adhesion to laminin, and severe defects in normal development. In 35% of cases, reduced levels of alpha 6 expression result in embryos that complete gastrulation normally but arrest at neurulation prior to the formation of the neural plate. In an additional 22% of cases, embryos develop with severe axial defects, including complete loss of head or tail structures. In contrast, overexpression of the alpha 6 subunit by injection of full-length mRNA has no apparent effect on embryonic development. Co-injection of antisense and sense plasmid constructs results in a partial rescue of the antisense-generated phenotypes. These data indicate that the integrin alpha 6 subunit is critical for the early development of the nervous system in amphibians.

Change in fetal behavior in response to vibroacoustic stimulation

2019 ◽  
Vol 47 (5) ◽  
pp. 558-563
Author(s):  
Kaoru Ogo ◽  
Kenji Kanenishi ◽  
Nobuhiro Mori ◽  
Mohamed Ahmed Mostafa AboEllail ◽  
Toshiyuki Hata
Keyword(s):  
Gestational Age ◽  
System Development ◽  
Age Groups ◽  
Arm Movement ◽  
Nervous System Development ◽  
Behavioral Changes ◽  
Age Group ◽  
4D Ultrasound ◽  
Before And After ◽  
Fetal Movements

Abstract Objective To assess fetal behavioral changes in response to vibroacoustic stimulation (VAS) in normal singleton pregnancies using four-dimensional (4D) ultrasound. Methods Ten types of fetal movements and facial expressions in 68 healthy pregnant women between 24 and 40 weeks were studied using 4D ultrasound for 3 min before and after 3-s VAS. The frequencies of mouthing, yawning, tongue expulsion, back arch, jerky arm movement, startle movement, smiling, scowling, hand-to-face movement, and blinking were evaluated. The fetuses were subdivided into four gestational age groups (24–27, 28–31, 32–35, and ≥36 weeks). Comparison of the frequencies of the fetal behaviors before and after the stimulation in each gestational age group was conducted to detect the response to stimulation with advancing gestation. Results There were no significant differences in the frequency of each fetal behavior before and after VAS at 24–27, 28–31, and 32–35 weeks of gestation. However, the frequencies of blinking and startle movements were significantly higher after VAS in the 36–40 gestational age group (P < 0.05). Conclusion The age of 36 weeks of gestation might represent an advanced stage of brain and central nervous system development and maturation as the response to stimuli is prominent at this age compared with earlier gestation.

scholarly journals Dpysl2 (CRMP2) is required for the migration of facial branchiomotor neurons in the developing zebrafish embryo

2020 ◽  
Vol 64 (10-11-12) ◽  
pp. 479-484
Author(s):  
Carolina Fiallos-Oliveros ◽  
Toshio Ohshima
Keyword(s):  
Motor Neurons ◽  
System Development ◽  
Nervous System Development ◽  
Knock Out ◽  
Facial Branchiomotor Neurons ◽  
Morpholino Oligonucleotides ◽  
Mutant Phenotypes ◽  
Antisense Morpholino Oligonucleotides

Dihydropyrimidinase-like family proteins (Dpysls) are relevant in several processes during nervous system development; among others, they are involved in axonal growth and cell migration. Dpysl2 (CRMP2) is the most studied member of this family; however, its role in vivo is still being investigated. Our previous studies in zebrafish showed the requirement of Dpysl2 for the proper positioning of caudal primary motor neurons and Rohon-Beard neurons in the spinal cord.In the present study, we show that Dpysl2 is necessary for the proper migration of facial branchiomotor neurons during early development in zebrafish. We generated a dpysl2 knock-out (KO) zebrafish mutant line and used different types of antisense morpholino oligonucleotides (AMO) to analyze the role of Dpysl2 in this process. Both dpysl2 KO mutants and morphants exhibited abnormalities in the migration of these neurons from rhombomers (r) 4 and 5 to 6 and 7. The facial branchiomotor neurons that were expected to be at r6 were still located at r4 and r5 hours after the migration process should have been completed. In addition, mutant phenotypes were rescued by injecting dpysl2 mRNA into the KO embryos. These results indicate that Dpysl2 is involved in the proper migration of facial branchiomotor neurons in developing zebrafish embryos.

scholarly journals TheC. elegansephrin EFN-4 functions non-cell autonomously with heparan sulfate proteoglycans to promote axon outgrowth and branching

2015 ◽  
Author(s):  
Alicia A Schwieterman ◽  
Alyse N Steves ◽  
Vivian Yee ◽  
Cory J Donelson ◽  
Aaron Pital ◽  
...  
Keyword(s):  
Nervous System ◽  
Neurite Outgrowth ◽  
Motor Neurons ◽  
System Development ◽  
Nervous System Development ◽  
The Body ◽  
Tissue Type ◽  
Eph Receptors ◽  
C Elegans ◽  
Core Proteins

The Eph receptors and their cognate ephrin ligands play key roles in many aspects of nervous system development. These interactions typically occur within an individual tissue type, serving either to guide axons to their terminal targets or to define boundaries between the rhombomeres of the hindbrain. We have identified a novel role for theCaenorhabditis elegansephrin EFN-4 in promoting primary neurite outgrowth in AIY interneurons and D-class motor neurons. Rescue experiments reveal that EFN-4 functions non-cell autonomously in the epidermis to promote primary neurite outgrowth. We also find that EFN-4 plays a role in promoting ectopic axon branching in aC. elegansmodel of X-linked Kallmann syndrome. In this context, EFN-4 functions non-cell autonomously in the body wall muscle, and in parallel with HS biosynthesis genes and HSPG core proteins, which function cell autonomously in the AIY neurons. This is the first report of an epidermal ephrin providing a developmental cue to the nervous system.

scholarly journals Gbx1 and Gbx2 Are Essential for Normal Patterning and Development of Interneurons and Motor Neurons in the Embryonic Spinal Cord

2020 ◽  
Vol 8 (2) ◽  
pp. 9
Author(s):  
Desirè M. Buckley ◽  
Jessica Burroughs-Garcia ◽  
Sonja Kriks ◽  
Mark Lewandoski ◽  
Samuel T. Waters
Keyword(s):  
Spinal Cord ◽  
Transcription Factors ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
System Development ◽  
Nervous System Development ◽  
Control Of Gene Expression ◽  
Spinal Cord Development ◽  
Ependymal Layer

The molecular mechanisms regulating neurogenesis involve the control of gene expression by transcription factors. Gbx1 and Gbx2, two members of the Gbx family of homeodomain-containing transcription factors, are known for their essential roles in central nervous system development. The expression domains of mouse Gbx1 and Gbx2 include regions of the forebrain, anterior hindbrain, and spinal cord. In the spinal cord, Gbx1 and Gbx2 are expressed in PAX2+ interneurons of the dorsal horn and ventral motor neuron progenitors. Based on their shared domains of expression and instances of overlap, we investigated the functional relationship between Gbx family members in the developing spinal cord using Gbx1−/−, Gbx2−/−, and Gbx1−/−/Gbx2−/− embryos. In situ hybridization analyses of embryonic spinal cords show upregulation of Gbx2 expression in Gbx1−/− embryos and upregulation of Gbx1 expression in Gbx2−/− embryos. Additionally, our data demonstrate that Gbx genes regulate development of a subset of PAX2+ dorsal inhibitory interneurons. While we observe no difference in overall proliferative status of the developing ependymal layer, expansion of proliferative cells into the anatomically defined mantle zone occurs in Gbx mutants. Lastly, our data shows a marked increase in apoptotic cell death in the ventral spinal cord of Gbx mutants during mid-embryonic stages. While our studies reveal that both members of the Gbx gene family are involved in development of subsets of PAX2+ dorsal interneurons and survival of ventral motor neurons, Gbx1 and Gbx2 are not sufficient to genetically compensate for the loss of one another. Thus, our studies provide novel insight to the relationship harbored between Gbx1 and Gbx2 in spinal cord development.

scholarly journals Reduced Hippocampal Brain-Derived Neurotrophic Factor (BDNF) in Neonatal Rats after Prenatal Exposure to Propylthiouracil (PTU)

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1311-1316 ◽  
Author(s):  
Goutam Chakraborty ◽  
Alejandra Magagna-Poveda ◽  
Carolyn Parratt ◽  
Jason G. Umans ◽  
Neil J. MacLusky ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Thyroid Hormone ◽  
Early Development ◽  
Neural Development ◽  
Neurotrophic Factor ◽  
System Development ◽  
Brain Derived Neurotrophic Factor ◽  
Experimental Models ◽  
Nervous System Development

Thyroid hormone is critical for central nervous system development. Fetal hypothyroidism leads to reduced cognitive performance in offspring as well as other effects on neural development in both humans and experimental animals. The nature of these impairments suggests that thyroid hormone may exert its effects via dysregulation of the neurotrophin brain-derived neurotrophic factor (BDNF), which is critical to normal development of the central nervous system and has been implicated in neurodevelopmental disorders. The only evidence of BDNF dysregulation in early development, however, comes from experimental models in which severe prenatal hypothyroidism occurred. By contrast, milder prenatal hypothyroidism has been shown to alter BDNF levels and BDNF-dependent functions only much later in life. We hypothesized that mild experimental prenatal hypothyroidism might lead to dysregulation of BDNF in the early postnatal period. BDNF levels were measured by ELISA at 3 or 7 d after birth in different regions of the brains of rats exposed to propylthiouracil (PTU) in the drinking water. The dose of PTU that was used induced mild maternal thyroid hormone insufficiency. Pups, but not the parents, exhibited alterations in tissue BDNF levels. Hippocampal BDNF levels were reduced at both d 3 and 7, but no significant reductions were observed in either the cerebellum or brain stem. Unexpectedly, more males than females were born to PTU-treated dams, suggesting an effect of PTU on sex determination. These results support the hypothesis that reduced hippocampal BDNF levels during early development may contribute to the adverse neurodevelopmental effects of mild thyroid hormone insufficiency during pregnancy.

Transcriptional profiling of iPSC-derived neurons with reciprocal monogenic CNV in 3p26.3 region

2020 ◽  
pp. 10-11
Author(s):  
М.Е. Лопаткина ◽  
В.С. Фишман ◽  
М.М. Гридина ◽  
Н.А. Скрябин ◽  
Т.В. Никитина ◽  
...  
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
System Development ◽  
Transcriptional Profiling ◽  
Global Gene Expression ◽  
Nervous System Development ◽  
Number Variation ◽  
The Central Nervous System ◽  
Cntn6 Gene ◽  
Copy Number Changes

Проведен анализ генной экспрессии в нейронах, дифференцированных из индуцированных плюрипотентных стволовых клеток пациентов с идиопатическими интеллектуальными нарушениями и реципрокными хромосомными мутациями в регионе 3p26.3, затрагивающими единственный ген CNTN6. Для нейронов с различным типом хромосомных аберраций была показана глобальная дисрегуляция генной экспрессии. В нейронах с вариациями числа копий гена CNTN6 была снижена экспрессия генов, продукты которых вовлечены в процессы развития центральной нервной системы. The gene expression analysis of iPSC-derived neurons, obtained from patients with idiopathic intellectual disability and reciprocal microdeletion and microduplication in 3p26.3 region affecting the single CNTN6 gene was performed. The global gene expression dysregulation was demonstrated for cells with CNTN6 copy number variation. Gene expression in neurons with CNTN6 copy number changes was downregulated for genes, whose products are involved in the central nervous system development.

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