Potential Effects of Low-Level Toluene Exposure on the Nervous System of Mothers and Infants.

In day-to-day living, individuals are exposed to various environmentally hazardous substances that have been associated with diverse diseases. Exposure to air pollutants can occur during breathing, posing a considerable risk to those with environmental health vulnerabilities. Among vulnerable individuals, maternal exposure can negatively impact the mother and child in utero. The developing fetus is particularly vulnerable to environmentally hazardous substances, with potentially greater implications. Among air pollutants, toluene is neurotoxic, and its effects have been widely explored. However, the impact of low-level toluene exposure in daily life remains unclear. Herein, we evaluated 194 mothers and infants from the Growing children's health and Evaluation of Environment (GREEN) cohort to determine the possible effects of early-life toluene exposure on the nervous system. Using Omics experiments, the effects of toluene were confirmed based on epigenetic changes and altered mRNA expression. Various epigenetic changes were identified, with upregulated expression potentially contributing to diseases such as glioblastoma and Alzheimer's, and downregulated expression being associated with structural neuronal abnormalities. These findings were detected in both maternal and infant groups, suggesting that maternal exposure to environmental hazardous substances can negatively impact the fetus. Our findings will facilitate the establishment of environmental health policies, including the management of environmentally hazardous substances for vulnerable groups.

The Acoel nervous system: morphology and development.

Acoel flatworms have played a relevant role in classical (and current) discussions on the evolutionary origin of bilaterian animals. This is mostly derived from the apparent simplicity of their body architectures. This tenet has been challenged over the last couple of decades, mostly because detailed studies of their morphology and the introduction of multiple genomic technologies have unveiled a complexity of cell types, tissular arrangements and patterning mechanisms that were hidden below this 'superficial' simplicity. One tissue that has received a particular attention has been the nervous system (NS). The combination of ultrastructural and single cell methodologies has revealed unique cellular diversity and developmental trajectories for most of their neurons and associated sensory systems. Moreover, the great diversity in NS architectures shown by different acoels offers us with a unique group of animals where to study key aspects of neurogenesis and diversification od neural systems over evolutionary time.In this review we revisit some recent developments in the characterization of the acoel nervous system structure and the regulatory mechanisms that contribute to their embryological development. We end up by suggesting some promising avenues to better understand how this tissue is organized in its finest cellular details and how to achieve a deeper knowledge of the functional roles that genes and gene networks play in its construction.

Unlocking the potential of SY-stem cells.

The sixth SY-Stem Symposium, jointly organized by the Research Institute of Molecular Pathology and the Institute of Molecular Biotechnology took place in Vienna in March 2024. Again, aspiring new group leaders were given a stage to present their work and vision of their labs. To round up the excellent program, the scientific organizers included renowned keynote speakers. Here, we provide a summary of the talks covering topics such as early embryogenesis, nervous system development and disease, regeneration and the latest technologies.

40†years of homeodomain transcription factors in the Drosophila nervous system.

Drosophila nervous system development progresses through a series of well-characterized steps in which homeodomain transcription factors (HDTFs) play key roles during most, if not all, phases. Strikingly, although some HDTFs have only one role, many others are involved in multiple steps of the developmental process. Most Drosophila HDTFs engaged in nervous system development are conserved in vertebrates and often play similar roles during vertebrate development. In this Spotlight, we focus on the role of HDTFs during embryogenesis, where they were first characterized.

Cell behaviors that pattern developing tissues: the case of the vertebrate nervous system.

Morphogenesis from cells to tissue gives rise to the complex architectures that make our organs. How cells and their dynamic behavior are translated into functional spatial patterns is only starting to be understood. Recent advances in quantitative imaging revealed that, although highly heterogeneous, cellular behaviors make reproducible tissue patterns. Emerging evidence suggests that mechanisms of cellular coordination, intrinsic variability and plasticity are critical for robust pattern formation. While pattern development shows a high level of fidelity, tissue organization has undergone drastic changes throughout the course of evolution. In addition, alterations in cell behavior, if unregulated, can cause developmental malformations that disrupt function. Therefore, comparative studies of different species and of disease models offer a powerful approach for understanding how novel spatial configurations arise from variations in cell behavior and the fundamentals of successful pattern formation. In this chapter, I dive into the development of the vertebrate nervous system to explore efforts to dissect pattern formation beyond molecules, the emerging core principles and open questions.

From bristle to brain: embryonic development of topographic projections from basiconic sensilla in the antennal nervous system of the locust Schistocerca gregaria.

The antennal flagellum of the locust S. gregaria is an articulated structure bearing a spectrum of sensilla that responds to sensory stimuli. In this study, we focus on the basiconic-type bristles as a model for sensory system development in the antenna. At the end of embryogenesis, these bristles are found at fixed locations and then on only the most distal six articulations of the antenna. They are innervated by a dendrite from a sensory cell cluster in the underlying epithelium, with each cluster directing fused axons topographically to an antennal tract running to the brain. We employ confocal imaging and immunolabeling to (a) identify mitotically active sense organ precursors for sensory cell clusters in the most distal annuli of the early embryonic antenna; (b) observe the subsequent spatial appearance of their neuronal progeny; and (c) map the spatial and temporal organization of axon projections from such clusters into the antennal tracts. We show that early in embryogenesis, proliferative precursors are localized circumferentially within discrete epithelial domains of the flagellum. Progeny first appear distally at the antennal tip and then sequentially in a proximal direction so that sensory neuron populations are distributed in an age-dependent manner along the antenna. Autotracing reveals that axon fasciculation with a tract is also sequential and reflects the location and age of the cell cluster along the most distal annuli. Cell cluster location and bristle location are therefore represented topographically and temporally within the axon profile of the tract and its projection to the brain.

Differential expression of the Tmem132 family genes in the developing mouse nervous system.

The family of novel transmembrane proteins (TMEM) 132 have been associated with multiple neurological disorders and cancers in humans, but have hardly been studied in vivo. Here we report the expression patterns of the five Tmem132 genes (a, b, c, d and e) in developing mouse nervous system with RNA in situ hybridization in wholemount embryos and tissue sections. Our results reveal differential and partially overlapping expression of multiple Tmem132 family members in both the central and peripheral nervous system, suggesting potential partial redundancy among them.

Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders.

The blood-brain barrier (BBB) protects the central nervous system (CNS) from harmful blood-borne factors. Although BBB dysfunction is a hallmark of several neurological disorders, therapies to restore BBB function are lacking. An attractive strategy is to repurpose developmental BBB regulators, such as Wnt7a, into BBB-protective agents. However, safe therapeutic use of Wnt ligands is complicated by their pleiotropic Frizzled signaling activities. Taking advantage of the Wnt7a/b-specific Gpr124/Reck co-receptor complex, we genetically engineered Wnt7a ligands into BBB-specific Wnt activators. In a "hit-and-run" adeno-associated virus-assisted CNS gene delivery setting, these new Gpr124/Reck-specific agonists protected BBB function, thereby mitigating glioblastoma expansion and ischemic stroke infarction. This work reveals that the signaling specificity of Wnt ligands is adjustable and defines a modality to treat CNS disorders by normalizing the BBB.

Spatiotemporal expression of IgLON family members in the developing mouse nervous system.

Differential expression of cell adhesion molecules in neuronal populations is one of the many mechanisms promoting the formation of functional neural circuits in the developing nervous system. The IgLON family consists of five cell surface immunoglobulin proteins that have been associated with various developmental disorders, such as autism spectrum disorder, schizophrenia, and major depressive disorder. However, there is still limited and fragmented information about their patterns of expression in certain regions of the developing nervous system and how their expression contributes to their function. Utilizing an in situ hybridization approach, we have analyzed the spatiotemporal expression of all IgLON family members in the developing mouse brain, spinal cord, eye, olfactory epithelium, and vomeronasal organ. At one prenatal (E16) and two postnatal (P0 and P15) ages, we show that each IgLON displays distinct expression patterns in the olfactory system, cerebral cortex, midbrain, cerebellum, spinal cord, and eye, indicating that they likely contribute to the wiring of specific neuronal circuitry. These analyses will inform future functional studies aimed at identifying additional roles for these proteins in nervous system development.

Parallels between the Developing Vascular and Neural Systems: Signaling Pathways and Future Perspectives for Regenerative Medicine.

Neurovascular disorders, which involve the vascular and nervous systems, are common. Research on such disorders usually focuses on either vascular or nervous components, without looking at how they interact. Adopting a neurovascular perspective is essential to improve current treatments. Therefore, comparing molecular processes known to be involved in both systems separately can provide insight into promising areas of future research. Since development and regeneration share many mechanisms, comparing signaling molecules involved in both the developing vascular and nervous systems and shedding light to those that they have in common can reveal processes, which have not yet been studied from a regenerative perspective, yet hold great potential. Hence, this review discusses and compares processes involved in the development of the vascular and nervous systems, in order to provide an overview of the molecular mechanisms, which are most promising with regards to treatment for neurovascular disorders. Vascular endothelial growth factor, semaphorins, and ephrins are found to hold the most potential, while fibroblast growth factor, bone morphogenic protein, slits, and sonic hedgehog are shown to participate in both the developing vascular and nervous systems, yet have not been studied at the neurovascular level, therefore being of special interest for future research.

Effects of Cannabinoid Exposure during Neurodevelopment on Future Effects of Drugs of Abuse: A Preclinical Perspective.

The endocannabinoid system plays a central role in the earliest stages of embryonic, postnatal and adolescent neurodevelopment. Aberrant activity of this system at key developmental phases has been shown to affect neural development. The aim of this review is to synthesise and analyse preclinical insights within rodent populations, focusing on the effects that perinatal (embryonic, gestational and early postnatal developmental stages) and adolescent (postnatal day 21-60) cannabinoid exposure impose across time on the subsequent activity of various drugs of abuse. Results in rodents show that exposure to cannabinoids during the perinatal and adolescent period can lead to multifaceted behavioural and molecular changes. In the perinatal period, significant effects of Δ9-THC exposure on subsequent opiate and amphetamine reward-related behaviours were observed primarily in male rodents. These effects were not extended to include cocaine or alcohol. In adolescence, various cannabinoid agonists were used experimentally. This array of cannabinoids demonstrated consistent effects on opioids across sex. In contrast, no significant effects were observed regarding the future activity of amphetamines and cocaine. However, these studies focused primarily on male rodents. In conclusion, numerous gaps and limitations are apparent in the current body of research. The sparsity of studies analysing the perinatal period must be addressed. Future research within both periods must also focus on delineating sex-specific effects, moving away from a male-centric focus. Studies should also aim to utilise more clinically relevant cannabinoid treatments.

Dynamic Expression of Membrane Type 1-Matrix Metalloproteinase (Mt1-mmp/Mmp14) in the Mouse Embryo.

MT1-MMP/MMP14 belongs to a subgroup of the matrix metalloproteinases family that presents a transmembrane domain, with a cytosolic tail and the catalytic site exposed to the extracellular space. Deficient mice for this enzyme result in early postnatal death and display severe defects in skeletal, muscle and lung development. By using a transgenic line expressing the LacZ reporter under the control of the endogenous Mt1-mmp promoter, we reported a dynamic spatiotemporal expression pattern for Mt1-mmp from early embryonic to perinatal stages during cardiovascular development and brain formation. Thus, Mt1-mmp shows expression in the endocardium of the heart and the truncus arteriosus by E8.5, and is also strongly detected during vascular system development as well as in endothelial cells. In the brain, LacZ reporter expression was detected in the olfactory bulb, the rostral cerebral cortex and the caudal mesencephalic tectum. LacZ-positive cells were observed in neural progenitors of the spinal cord, neural crest cells and the intersomitic region. In the limb, Mt1-mmp expression was restricted to blood vessels, cartilage primordium and muscles. Detection of the enzyme was confirmed by Western blot and immunohistochemical analysis. We suggest novel functions for this metalloproteinase in angiogenesis, endocardial formation and vascularization during organogenesis. Moreover, Mt1-mmp expression revealed that the enzyme may contribute to heart, muscle and brain throughout development.

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.

Role of BMP signaling during early development of the annelid Capitella teleta.

The mechanisms regulating nervous system development are still unknown for a wide variety of taxa. In insects and vertebrates, bone morphogenetic protein (BMP) signaling plays a key role in establishing the dorsal-ventral (D-V) axis and limiting the neuroectoderm to one side of that axis, leading to speculation about the conserved evolution of centralized nervous systems. Studies outside of insects and vertebrates show a more diverse picture of what, if any role, BMP signaling plays in neural development across Bilateria. This is especially true in the morphologically diverse Spiralia (≈Lophotrochozoa). Despite several studies of D-V axis formation and neural induction in spiralians, there is no consensus for how these two processes are related, or whether BMP signaling may have played an ancestral role in either process. To determine the function of BMP signaling during early development of the spiralian annelid Capitella teleta, we incubated embryos and larvae in BMP4 protein for different amounts of time. Adding exogenous BMP protein to early-cleaving C. teleta embryos had a striking effect on formation of the brain, eyes, foregut, and ventral midline in a time-dependent manner. However, adding BMP did not block brain or VNC formation or majorly disrupt the D-V axis. We identified three key time windows of BMP activity. 1) BMP treatment around birth of the 3rd-quartet micromeres caused the loss of the eyes, radialization of the brain, and a reduction of the foregut, which we interpret as a loss of A- and C-quadrant identities with a possible trans-fate switch to a D-quadrant identity. 2) Treatment after the birth of micromere 4d induced formation of a third ectopic brain lobe, eye, and foregut lobe, which we interpret as a trans-fate switch of B-quadrant micromeres to a C-quadrant identity. 3) Continuous BMP treatment from late cleavage (4d â€‹+ â€‹12 â€‹h) through mid-larval stages resulted in a modest expansion of Ct-chrdl expression in the dorsal ectoderm and a concomitant loss of the ventral midline (neurotroch ciliary band). Loss of the ventral midline was accompanied by a collapse of the bilaterally-symmetric ventral nerve cord, although the total amount of neural tissue was not greatly affected. Our results compared with those from other annelids and molluscs suggest that BMP signaling was not ancestrally involved in delimiting neural tissue to one region of the D-V axis. However, the effects of ectopic BMP on quadrant-identity during cleavage stages may represent a non-axial organizing signal that was present in the last common ancestor of annelids and mollusks. Furthermore, in the last common ancestor of annelids, BMP signaling may have functioned in patterning ectodermal fates along the D-V axis in the trunk. Ultimately, studies on a wider range of spiralian taxa are needed to determine the role of BMP signaling during neural induction and neural patterning in the last common ancestor of this group. Ultimately, these comparisons will give us insight into the evolutionary origins of centralized nervous systems and body plans.

Perspective on prenatal polychlorinated biphenyl exposure and the development of the progeny nervous system (Review).

The developmental origins of health and disease concept illustrates that exposure in early life to various factors may affect the offspring's long­term susceptibility to disease. During development, the nervous system is sensitive and vulnerable to the environmental insults. Polychlorinated biphenyls (PCBs), which are divided into dioxin­like (DL­PCBs) and non­dioxin­like PCBs (NDL­PCBs), are synthetic persistent environmental endocrine­disrupting chemicals. The toxicological mechanisms of DL­PCBs have been associated with the activation of the aryl hydrocarbon receptor and NDL­PCBs have been associated with ryanodine receptor­mediated calcium ion channels, which affect neuronal migration, promote dendritic growth and alter neuronal connectivity. In addition, PCB accumulation in the placenta destroys the fetal placental unit and affects endocrine function, particularly thyroid hormones and the dopaminergic system, leading to neuroendocrine disorders. However, epidemiological investigations have not achieved a consistent result in different study cohorts. The present review summarizes the epidemiological differences and possible mechanisms of the effects of intrauterine PCB exposure on neurological development.

Parallel Rap1>RalGEF>Ral and Ras signals sculpt the C. elegans nervous system.

Ras is the most commonly mutated oncogene in humans and uses three oncogenic effectors: Raf, PI3K, and RalGEF activation of Ral. Understanding the importance of RalGEF>Ral signaling in cancer is hampered by the paucity of knowledge about their function in animal development, particularly in cell movements. We found that mutations that disrupt function of RalGEF or Ral enhance migration phenotypes of mutants for genes with established roles in cell migration. We used as a model the migration of the canal associated neurons (CANs), and validated our results in HSN cell migration, neurite guidance, and general animal locomotion. These functions of RalGEF and Ral are specific to their control of Ral signaling output rather than other published functions of these proteins. In this capacity Ral functions cell autonomously as a permissive developmental signal. In contrast, we observed Ras, the canonical activator of RalGEF>Ral signaling in cancer, to function as an instructive signal. Furthermore, we unexpectedly identified a function for the close Ras relative, Rap1, consistent with activation of RalGEF>Ral. These studies define functions of RalGEF>Ral, Rap1 and Ras signaling in morphogenetic processes that fashion the nervous system. We have also defined a model for studying how small GTPases partner with downstream effectors. Taken together, this analysis defines novel molecules and relationships in signaling networks that control cell movements during development of the nervous system.

Comparative Neurodevelopment Effects of Bisphenol A and Bisphenol F on Rat Fetal Neural Stem Cell Models.

Bisphenol A (BPA) is considered as one of the most extensively synthesized and used chemicals for industrial and consumer products. Previous investigations have established that exposure to BPA has been linked to developmental, reproductive, cardiovascular, immune, and metabolic effects. Several jurisdictions have imposed restrictions and/or have banned the use of BPA in packaging material and other consumer goods. Hence, manufacturers have replaced BPA with its analogues that have a similar chemical structure. Some of these analogues have shown similar endocrine effects as BPA, while others have not been assessed. In this investigation, we compared the neurodevelopmental effects of BPA and its major replacement Bisphenol F (BPF) on rat fetal neural stem cells (rNSCs). rNSCs were exposed to cell-specific differentiation media with non-cytotoxic doses of BPA or BPF at the range of 0.05 M to 100 M concentrations and measured the degree of cell proliferation, differentiation, and morphometric parameters. Both of these compounds increased cell proliferation and impacted the differentiation rates of oligodendrocytes and neurons, in a concentration-dependent manner. Further, there were concentration-dependent decreases in the maturation of oligodendrocytes and neurons, with a concomitant increase in immature oligodendrocytes and neurons. In contrast, neither BPA nor BPF had any overall effect on cellular proliferation or the cytotoxicity of astrocytes. However, there was a concentration-dependent increase in astrocyte differentiation and morphological changes. Morphometric analysis for the astrocytes, oligodendrocytes, and neurons showed a reduction in the arborization. These data show that fetal rNSCs exposed to either BPA or BPF lead to comparable changes in the cellular differentiation, proliferation, and arborization processes.

Recurrent Implication of Striatal Cholinergic Interneurons in a Range of Neurodevelopmental, Neurodegenerative, and Neuropsychiatric Disorders.

Cholinergic interneurons are "gatekeepers" for striatal circuitry and play pivotal roles in attention, goal-directed actions, habit formation, and behavioral flexibility. Accordingly, perturbations to striatal cholinergic interneurons have been associated with many neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. The role of acetylcholine in many of these disorders is well known, but the use of drugs targeting cholinergic systems fell out of favor due to adverse side effects and the introduction of other broadly acting compounds. However, in response to recent findings, re-examining the mechanisms of cholinergic interneuron dysfunction may reveal key insights into underlying pathogeneses. Here, we provide an update on striatal cholinergic interneuron function, connectivity, and their putative involvement in several disorders. In doing so, we aim to spotlight recurring physiological themes, circuits, and mechanisms that can be investigated in future studies using new tools and approaches.

Dysregulation of Multiple Signaling Neurodevelopmental Pathways during Embryogenesis: A Possible Cause of Autism Spectrum Disorder.

Understanding the autistic brain and the involvement of genetic, non-genetic, and numerous signaling pathways in the etiology and pathophysiology of autism spectrum disorder (ASD) is complex, as is evident from various studies. Apart from multiple developmental disorders of the brain, autistic subjects show a few characteristics like impairment in social communications related to repetitive, restricted, or stereotypical behavior, which suggests alterations in neuronal circuits caused by defects in various signaling pathways during embryogenesis. Most of the research studies on ASD subjects and genetic models revealed the involvement of mutated genes with alterations of numerous signaling pathways like Wnt, hedgehog, and Retinoic Acid (RA). Despite significant improvement in understanding the pathogenesis and etiology of ASD, there is an increasing awareness related to it as well as a need for more in-depth research because no effective therapy has been developed to address ASD symptoms. Therefore, identifying better therapeutic interventions like "novel drugs for ASD" and biomarkers for early detection and disease condition determination are required. This review article investigated various etiological factors as well as the signaling mechanisms and their alterations to understand ASD pathophysiology. It summarizes the mechanism of signaling pathways, their significance, and implications for ASD.

Altered sacral neural crest development in Pax3 spina bifida mutants underlies deficits of bladder innervation and function.

Mouse models of Spina bifida (SB) have been instrumental for identifying genes, developmental processes, and environmental factors that influence neurulation and neural tube closure. Beyond the prominent neural tube defects, other aspects of the nervous system can be affected in SB with significant changes in essential bodily functions such as urination. SB patients frequently experience bladder dysfunction and SB fetuses exhibit reduced density of bladder nerves and smooth muscle although the developmental origins of these deficits have not been determined. The Pax3 Splotch-delayed (Pax3Sp-d) mouse model of SB is one of a very few mouse SB models that survives to late stages of gestation. Through analysis of Pax3Sp-d mutants we sought to define how altered bladder innervation in SB might arise by tracing sacral neural crest (NC) development, pelvic ganglia neuronal differentiation, and assessing bladder nerve fiber density. In Pax3Sp-d/Sp-d fetal mice we observed delayed migration of Sox10+ NC-derived progenitors (NCPs), deficient pelvic ganglia neurogenesis, and reduced density of bladder wall innervation. We further combined NC-specific deletion of Pax3 with the constitutive Pax3Sp-d allele in an effort to generate viable Pax3 mutants to examine later stages of bladder innervation and postnatal bladder function. Neural crest specific deletion of a Pax3 flox allele, using a Sox10-cre driver, in combination with a constitutive Pax3Sp-d mutation produced postnatal viable offspring that exhibited altered bladder function as well as reduced bladder wall innervation and altered connectivity between accessory ganglia at the bladder neck. Combined, the results show that Pax3 plays critical roles within sacral NC that are essential for initiation of neurogenesis and differentiation of autonomic neurons within pelvic ganglia.