Roots of the Malformations of Cortical Development in the Cell Biology of Neural Progenitor Cells

The cerebral cortex is a structure that underlies various brain functions, including cognition and language. Mammalian cerebral cortex starts developing during the embryonic period with the neural progenitor cells generating neurons. Newborn neurons migrate along progenitors’ radial processes from the site of their origin in the germinal zones to the cortical plate, where they mature and integrate in the forming circuitry. Cell biological features of neural progenitors, such as the location and timing of their mitoses, together with their characteristic morphologies, can directly or indirectly regulate the abundance and the identity of their neuronal progeny. Alterations in the complex and delicate process of cerebral cortex development can lead to malformations of cortical development (MCDs). They include various structural abnormalities that affect the size, thickness and/or folding pattern of the developing cortex. Their clinical manifestations can entail a neurodevelopmental disorder, such as epilepsy, developmental delay, intellectual disability, or autism spectrum disorder. The recent advancements of molecular and neuroimaging techniques, along with the development of appropriate in vitro and in vivo model systems, have enabled the assessment of the genetic and environmental causes of MCDs. Here we broadly review the cell biological characteristics of neural progenitor cells and focus on those features whose perturbations have been linked to MCDs.

Effects of Selective Alveolar Decortication on the Periodontal Complex

Background Modification of bone turnover has been reported following selective alveolar decortication but the molecular signals in the periodontal ligament space (PDL) remain unanswered. The objective of this study was to understand how selective alveolar decortication affects the biological reactions in the periodontal ligament. Methods Selective alveolar decortication in wild-type mice (n=25) was performed on mandibular right buccal cortical plate adjacent to the mandibular right third molar and euthanized at 3, 7, 14 and 28 days. We also performed selective alveolar decortication in Lrp5ACT (n=5) mice and Ad-Dkk1 treated mice (n=5), and euthanized at 7 days. The periodontium around the mandibular third molars were examined using histology, immunohistochemical analyses for osteogenic markers, TGF-β, RANKL, TRAP and alkaline phosphatase activity. Results The expression of osteogenic markers in the wild-type PDL was maintained during healing time period after selective alveolar decortication. Increased osteoclast activity in the wild-type mice was observed at 3 and 7 days after selective alveolar decortication. The PDL in Lrp5G171V (Lrp5ACT) mice and adenovirus Dkk1 (Ad-Dkk1) treated mice also showed insignificant changes in the expression of osteogenic markers following selective alveolar decortication. In Lrp5ACT mice where there was a reduction of bone resorption, selective alveolar decortication caused a dramatic increase in osteoclast activity. Conclusions Selective alveolar decortication affects only bone turnover, but not the expression of osteogenic markers in the PDL.

Carboxypeptidase E Independently Changes Microtubule Glutamylation, Dendritic Branching, and Neuronal Migration

Neuronal migration and dendritogenesis are dependent on dynamic changes to the microtubule (MT) network. Among various factors that regulate MT dynamics and stability, post-translational modifications (PTMs) of MTs play a critical role in conferring specificity of regulatory protein binding to MTs. Thus, it is important to understand the regulation of PTMs during brain development as multiple developmental processes are dependent on MTs. In this study, we identified that carboxypeptidase E (CPE) changes tubulin polyglutamylation, a major PTM in the brain, and we examine the impact of CPE-mediated changes to polyglutamylation on cortical neuron migration and dendrite morphology. We show, for the first time, that overexpression of CPE increases the level of polyglutamylated α-tubulin while knockdown decreases the level of polyglutamylation. We also demonstrate that CPE-mediated changes to polyglutamylation are dependent on the CPE zinc-binding motif and that this motif is necessary for CPE action on p150Glued localization. However, overexpression of a CPE mutant that does not increase MT glutamylation mimics the effects of overexpression of wild type CPE on dendrite branching. Furthermore, although overexpression of wild type CPE does not alter cortical neuron migration, overexpression of the mutant may act in a dominant-negative manner as it decreases the number of neurons that reach the cortical plate (CP), as we previously reported for CPE knockdown. Overall, our data suggest that CPE changes MT glutamylation and redistribution of p150Glued and that this function of CPE is independent of its role in shaping dendrite development but plays a partial role in regulating cortical neuron migration.

Severe fetal symptomatic infection from human cytomegalovirus following non-primary maternal infection: report of two cases

Introduction Human cytomegalovirus (HCMV) is the most common congenital infection, expecially severe after a maternal primary infection; sequelae in neonates born to mothers experiencing a non-primary infection have been already reported. Hereby, two cases of severe fetal HCMV disease in seroimmune gravidas referred to our Unit are described. Cases presentation Case 1 A fetus at 21 weeks’ gestation with signs of anemia and brain abnormalities at ultrasound (US), described at magnetic resonance (MR) imaging as ependymal irregularity and bilateral asymmetric parenchimal thinning; amniotic fluid sample was positive for HCMV although the woman had a previous immunity; after termination of pregnancy, autopsy demonstrated a thicken layer of disorganized neurons on the right cortical plate, while on the left there was a morphological pattern coherent with polymicrogyria. Case 2 A fetus at 20 weeks’ gestation with anemia, moderate atrio-ventricular insufficiency, hepatosplenomegaly but no major cerebral lesions. Fetal blood was positive for HCMV, although unexpected for pre-pregnancy maternal immunity, and intrauterine transfusion was needed. A cesarean section at 34 weeks gestation was performed due to worsening condition of the fetus, who had a birthweight of 2210 grams, needed platelet transfusions but MR examination and clinical evaluation were normal. Conclusion The impact of non-primary maternal infection on pregnancy outcome is unknown and fetal brain damage in HCMV seroimmune transmitter-mothers can occur as a consequence of maternal re-infection or reactivation for a hypotetic different role of HCMV-primed CD4+ or CD8+ T-cells in fetal brain, with progressive brain lesions coexistent in the first case and with severe unexpected anemia in the second case. A previous maternal HCMV immunity should not exempt to test anemic fetuses for such infection, nor to consider a potential transplacental transmission.

Surgical management of central giant cell granuloma of mandible and prosthetic rehabilitation in a nine year girl: A case report

Central giant cell granuloma (CGCG) is an uncommon, benign, idiopathic, osteolytic lesion of jaws, histologically characterized by multinucleated giant cells distributed in fibrovascular connective tissue stroma. Accurate diagnosis of the lesion is essential for the successful management and the prognosis of this locally destructive lesion. In this paper, a rare case of large destructive CGCG involving anterior region of mandible, causing expansion of labial cortical plate and mobility of teeth in a nine-year girl is presented. It was treated successfully by enucleation and curettage with satisfactory preservation of the continuity of mandible. Nine months post operatively, the child was rehabilitated with a temporary partial denture to improve esthetics, phonetics and function. One year clinical and radiographic follow up showed new bone formation and no evidence of recurrence.

Interradicular distance and alveolar bone thickness for miniscrew insertion: a CBCT study of Persian adults with different sagittal skeletal patterns

Background This study aimed to assess the interradicular distance and alveolar bone thickness of Persian adults with different sagittal skeletal patterns for miniscrew insertion using cone-beam computed tomography (CBCT). Methods This cross-sectional study was conducted on maxillary and mandibular CBCT scans of 60 patients (18–35 years) in three groups (n = 20) of class I, II and III sagittal skeletal pattern. Anatomical and skeletal parameters were measured at 2, 4 and 6 mm apical to the cementoenamel junction (CEJ) by one examiner. The intra- and inter-class correlation coefficients were calculated to assess the intra, and interobserver reliability. Data were analyzed by ANOVA and Tukey’s test (alpha = 0.05). Results The intra- and interobserver reliability were > 0.9 for all parameters. The largest inter-radicular distance in the maxilla was between the central incisors (1–1) in classes I and III, and between premolars (4–5) in class II patients. The largest inter-radicular distance in the mandible was between molar teeth (6–7) in all three classes. The buccal cortical plate thickness was maximum at the site of mandibular first and second molars (6–7). The posterior maxilla and mandible showed the maximum thickness of cancellous bone and alveolar process. Wide variations were noted in this respect between class I, II and III patients. Conclusions The area with maximum inter-radicular distance and optimal alveolar bone thickness for miniscrew insertion varies in different individuals, depending on their sagittal skeletal pattern.

Prong maxillary complete denture for better facial aesthetic: A case report

Denture teeth and denture flange are two very important aspects of a complete denture. For aesthetic purpose while fabricating the complete denture prosthesis, restoring the labial fullness is a sensitive procedure. There are some clinical situations where the labial flange gives poor facial aesthetics. It is more occur in proclined maxillary anterior ridge or thick labial cortical plate with severe labial undercut. In this article we are presenting a case with thick labial cortical plates and severe labial undercut. So, we have modified the complete denture and delivered a prong (flangeless) denture to give more aesthetic appearance to the patient.

From compartments to gene loops: Functions of the 3D genome in the human brain

The 3D genome plays a key role in the regulation of gene expression. However, little is known about the spatiotemporal organization of chromatin during human brain development. We investigated the 3D genome in human fetal cortical plate and in adult prefrontal cortical neurons and glia. We found that neurons have weaker compartments than glia that emerge during fetal development. Furthermore, neurons form loop domains whereas glia form compartment domains. We show through CRISPRi on CNTNAP2 that transcription is coupled to loop domain insulation. Gene regulation during neural development involves increased use of enhancer-promoter and repressor-promoter loops. Finally, transcription is associated with gene loops. Altogether, we provide novel insights into the relationship between gene expression and different scales of chromatin organization in the human brain.

Blocking Placental Class G Immunoglobulin Transfer Prevents NMDA Receptor Antibody Effects in Newborn Mice

Background and ObjectivesTo determine in a mouse model whether neonatal Fc receptor (FcRn) blockade prevents the placental transfer of class G immunoglobulin (IgG) derived from patients with anti-NMDA receptor (NMDAR) encephalitis and their pathogenic effects on the fetuses and offspring.MethodsPregnant C57BL/6J mice were administered via tail vein FcRn antibody (FcRn-ab) or saline solution 6 hours before administration of patients' or controls' IgG on days 14, 15, and 16 of gestation. Three experimental groups were established: mice receiving controls' IgG, patients' IgG, or patients' IgG along with pretreatment with FcRn-ab. Immunohistochemical staining, confocal microscopy, hippocampal long-term potentiation, and standardized developmental and behavioral tasks were used to assess the efficacy of treatment with FcRn-ab.ResultsIn pregnant mice that received patients' IgG, treatment with FcRn-ab prevented the IgG from reaching the fetal brain, abrogating the decrease of NMDAR clusters and the reduction of cortical plate thickness that were observed in fetuses from untreated pregnant mice. Moreover, among the offspring of mothers that received patients' IgG, those whose mothers were treated with FcRn-ab did not develop the alterations that occurred in offspring of untreated mothers, including impairment in hippocampal plasticity, delay in innate reflexes, and visuospatial memory deficits.DiscussionFcRn blockade prevents placental transfer of IgG from patients with anti-NMDAR encephalitis and abrogates the synaptic and neurodevelopmental alterations caused by patients' antibodies. This model has potential therapeutic implications for other antibody-mediated diseases of the CNS during pregnancy.