Neural Cell Development Research Articles

Induced Pluripotent Stem Cells for Treatment of Alzheimer's and Parkinson's Diseases.

Neurodegenerative diseases are a group of debilitating pathologies in which neuronal tissue dies due to the buildup of neurotoxic plaques, resulting in detrimental effects on cognitive ability, motor control, and everyday function. Stem cell technology offers promise in addressing this problem on multiple fronts, but the conventional sourcing of pluripotent stem cells involves harvesting from aborted embryonic tissue, which comes with strong ethical and practical concerns. The keystone discovery of induced pluripotent stem cell (iPSC) technology provides an alternative and endless source, circumventing the unfavorable issues with embryonic stem cells, and yielding fundamental advantages. This review highlights iPSC technology, the pathophysiology of two major neurodegenerative diseases, Alzheimer’s and Parkinson’s, and then illustrates current state-of-the-art approaches towards the treatment of the diseases using iPSCs. The technologies discussed in the review emphasize in vitro therapeutic neural cell and organoid development for disease treatment, pathological modeling of neurodegenerative diseases, and 3D bioprinting as it applies to both.

Iron supplementation of breastfed Gambian infants from 6 weeks to 6 months of age: protocol for a randomised controlled trial.

Background: A recent analysis showed that plasma iron concentrations decline rapidly from birth in Gambian infants, irrespective of sex or birthweight, to concentrations well below normal expected values for iron-replete children older than two months of age (typically >10 μmol/L). The development and function of neural and immune cells may thus be compromised before the minimum age at which children should receive iron supplementation as per World Health Organisation recommendations. Methods: This study is a two-arm, double-blind, placebo-controlled, randomised superiority trial. Infants will be randomised to receive iron drops (7.5mg/day of iron as ferrous sulphate) or placebo daily for 98 days, to test the impact on serum iron concentrations in healthy, breastfed infants (n = 100) aged 6-10 weeks at enrolment. Participants will be visited daily and supplemented by the field team. Daily health and weekly breastfeeding questionnaires will be administered. Anthropometry, and venous blood and faecal samples will be collected at enrolment and after 98 days of supplementation with serum iron as the primary endpoint. Low birthweight (less than 2.5kg at birth) and infants born prematurely (< 37 weeks) will not be excluded. Formula-fed and infants with any illness will be excluded. An additional study exploring maternal stakeholder perspectives of the intervention will be conducted by means of maternal interviews and four focus group discussions with local stakeholders. Discussion: Most breast-fed Gambian infants have very low circulating iron levels by five months of age. This study will introduce iron supplements much earlier in infancy than has previously been attempted in a low-income setting with the primary aim of increasing serum iron concentration. Trial registration: Clincaltrials.gov ( NCT04751994); 12 th February 2021.

The Anti-Inflammatory Agent Bindarit Attenuates the Impairment of Neural Development through Suppression of Microglial Activation in a Neonatal Hydrocephalus Mouse Model.

Neonatal hydrocephalus presents with various degrees of neuroinflammation and long-term neurologic deficits in surgically treated patients, provoking a need for additional medical treatment. We previously reported elevated neuroinflammation and severe periventricular white matter damage in the progressive hydrocephalus (prh) mutant which contains a point mutation in the Ccdc39 gene, causing loss of cilia-mediated unidirectional CSF flow. In this study, we identified cortical neuropil maturation defects such as impaired excitatory synapse maturation and loss of homeostatic microglia, and swimming locomotor defects in early postnatal prh mutant mice. Strikingly, systemic application of the anti-inflammatory small molecule bindarit significantly supports healthy postnatal cerebral cortical development in the prh mutant. While bindarit only mildly reduced the ventricular volume, it significantly improved the edematous appearance and myelination of the corpus callosum. Moreover, the treatment attenuated thinning in cortical Layers II-IV, excitatory synapse formation, and interneuron morphogenesis, by supporting the ramified-shaped homeostatic microglia from excessive cell death. Also, the therapeutic effect led to the alleviation of a spastic locomotor phenotype of the mutant. We found that microglia, but not peripheral monocytes, contribute to amoeboid-shaped activated myeloid cells in prh mutants' corpus callosum and the proinflammatory cytokines expression. Bindarit blocks nuclear factor (NF)-kB activation and its downstream proinflammatory cytokines, including monocyte chemoattractant protein-1, in the prh mutant. Collectively, we revealed that amelioration of neuroinflammation is crucial for white matter and neuronal maturation in neonatal hydrocephalus. Future studies of bindarit treatment combined with CSF diversion surgery may provide long-term benefits supporting neuronal development in neonatal hydrocephalus.SIGNIFICANCE STATEMENT In neonatal hydrocephalus, little is known about the signaling cascades of neuroinflammation or the impact of such inflammatory insults on neural cell development within the perinatal cerebral cortex. Here, we report that proinflammatory activation of myeloid cells, the majority of which are derived from microglia, impairs periventricular myelination and cortical neuronal maturation using the mouse prh genetic model of neonatal hydrocephalus. Administration of bindarit, an anti-inflammatory small molecule that blocks nuclear factor (NF)-kB activation, restored the cortical thinning and synaptic maturation defects in the prh mutant brain through suppression of microglial activation. These data indicate the potential therapeutic use of anti-inflammatory reagents targeting neuroinflammation in the treatment of neonatal hydrocephalus.

Tocotrienols protect differentiated SH-SY5Y human neuroblastoma cells against 6-hydroxydopamine-induced cytotoxicity by ameliorating dopamine biosynthesis and dopamine receptor D2 gene expression

Oxidative stress is a critical factor that triggers a “domino” cascade of events leading to the degeneration of dopaminergic neurons in Parkinson disease. Tocotrienols (T3) have antioxidant effects and can protect neuronal cells against oxidative damage. In the present study, we investigated the neuroprotective effects of different forms of T3 (alpha, delta, gamma) or tocotrienol-rich fraction (TRF) against 6-hydroxydopamine (6-OHDA)-induced oxidative damage in differentiated SH-SY5Y human neural cells. Differentiating the SH-SY5Y cells with retinoic acid and a low-serum culture medium for 6 days allowed development of human dopamine-like neural cells. Subsequently, the differentiated SH-SY5Y neural cells were pretreated with different forms of T3 for 24 hours before these cells were exposed to 6-OHDA. The T3 analogues and TRF displayed neuroprotective effects (P < .05) via restoration of cell viability and activation of antioxidant enzymes (e.g., superoxide dismutase, catalase). Notably, TRF was highly efficient in scavenging reactive oxygen species and upregulating dopamine and tyrosine hydroxylase levels in the differentiated SH-SY5Y cells. Gamma-T3 exhibited the most potent effects in attenuating apoptosis, whereas alpha-T3 was most effective in preventing 6-OHDA-induced leakage of α-Synuclein. Delta-T3 displayed a noticeable effect in upregulating the dopamine receptor D2 gene expression compared with controls. These findings suggest T3 isoforms and TRF demonstrate significant neuroprotective effects in protecting differentiated neural cells against 6-OHDA-mediated oxidative stress.

Mechanism of annexin A6 promoting differentiation and development of neural progenitor cells into oligodendrocytes

Mechanism of annexin A6 promoting differentiation and development of neural progenitor cells into oligodendrocytes

Age-related neurodegeneration and cognitive impairments of NRMT1 knockout mice are preceded by misregulation of RB and abnormal neural stem cell development

N-terminal methylation is an important posttranslational modification that regulates protein/DNA interactions and plays a role in many cellular processes, including DNA damage repair, mitosis, and transcriptional regulation. Our generation of a constitutive knockout mouse for the N-terminal methyltransferase NRMT1 demonstrated its loss results in severe developmental abnormalities and premature aging phenotypes. As premature aging is often accompanied by neurodegeneration, we more specifically examined how NRMT1 loss affects neural pathology and cognitive behaviors. Here we find that Nrmt1−/− mice exhibit postnatal enlargement of the lateral ventricles, age-dependent striatal and hippocampal neurodegeneration, memory impairments, and hyperactivity. These morphological and behavior abnormalities are preceded by alterations in neural stem cell (NSC) development. Early expansion and differentiation of the quiescent NSC pool in Nrmt1−/− mice is followed by its subsequent depletion and many of the resulting neurons remain in the cell cycle and ultimately undergo apoptosis. These cell cycle phenotypes are reminiscent to those seen with loss of the NRMT1 target retinoblastoma protein (RB). Accordingly, we find misregulation of RB phosphorylation and degradation in Nrmt1−/− mice, and significant de-repression of RB target genes involved in cell cycle. We also identify novel de-repression of Noxa, an RB target gene that promotes apoptosis. These data identify Nα-methylation as a novel regulatory modification of RB transcriptional repression during neurogenesis and indicate that NRMT1 and RB work together to promote NSC quiescence and prevent neuronal apoptosis.

Potential Common Genetic Risks of Sporadic Parkinson's Disease and Amyotrophic Lateral Sclerosis in the Han Population of Mainland China.

Sporadic Parkinson’s disease (sPD) and sporadic amyotrophic lateral sclerosis (sALS) are neurodegenerative diseases characterized by progressive and selective neuron death, with some genetic similarities. In order to investigate the genetic risk factors common to both sPD and sALS, we carried out a screen of risk alleles for sALS and related loci in 530 sPD patients and 530 controls from the Han population of Mainland China (HPMC). We selected 27 single-nucleotide polymorphisms in 10 candidate genes associated with sALS, and we performed allelotyping and genotyping to determine their frequencies in the study population as well as bioinformatics analysis to assess their functional significance in these diseases. The minor alleles of rs17115303 in DAB adaptor protein 1 (DAB1) gene and rs6030462 in protein tyrosine phosphatase receptor type T (PTPRT) gene were correlated with increased risk of both sPD and sALS. Polymorphisms of rs17115303 and rs6030462 were associated with alterations in transcription factor binding sites, secondary structures, long non-coding RNA interactions, and nervous system regulatory networks; these changes involved biological processes associated with neural cell development, differentiation, neurogenesis, migration, axonogenesis, cell adhesion, and metabolism of phosphate-containing compounds. Thus, variants of DAB1 gene (rs17115303) and PTPRT gene (rs6030462) are risk factors common to sPD and sALS in the HPMC. These findings provide insight into the molecular pathogenesis of both diseases and can serve as a basis for the development of targeted therapies.

Global Transcriptional Analyses of the Wnt-Induced Development of Neural Stem Cells from Human Pluripotent Stem Cells.

The differentiation of human pluripotent stem cells (hPSCs) to neural stem cells (NSCs) is the key initial event in neurogenesis and is thought to be dependent on the family of Wnt growth factors, their receptors and signaling proteins. The delineation of the transcriptional pathways that mediate Wnt-induced hPSCs to NSCs differentiation is vital for understanding the global genomic mechanisms of the development of NSCs and, potentially, the creation of new protocols in regenerative medicine. To understand the genomic mechanism of Wnt signaling during NSCs development, we treated hPSCs with Wnt activator (CHIR-99021) and leukemia inhibitory factor (LIF) in a chemically defined medium (N2B27) to induce NSCs, referred to as CLNSCs. The CLNSCs were subcultured for more than 40 passages in vitro; were positive for AP staining; expressed neural progenitor markers such as NESTIN, PAX6, SOX2, and SOX1; and were able to differentiate into three neural lineage cells: neurons, astrocytes, and oligodendrocytes in vitro. Our transcriptome analyses revealed that the Wnt and Hedgehog signaling pathways regulate hPSCs cell fate decisions for neural lineages and maintain the self-renewal of CLNSCs. One interesting network could be the deregulation of the Wnt/β-catenin signaling pathway in CLNSCs via the downregulation of c-MYC, which may promote exit from pluripotency and neural differentiation. The Wnt-induced spinal markers HOXA1-4, HOXA7, HOXB1-4, and HOXC4 were increased, however, the brain markers FOXG1 and OTX2, were absent in the CLNSCs, indicating that CLNSCs have partial spinal cord properties. Finally, a CLNSC simple culture condition, when applied to hPSCs, supports the generation of NSCs, and provides a new and efficient cell model with which to untangle the mechanisms during neurogenesis.

Deciphering the Role of Fluctuation Dependent Intercellular Communication in Neural Stem Cell Development.

Neural stem cells (NPCs) efficiently communicate in an intercellular manner to govern specific cell fate decisions during the developmental process despite withstanding the fluctuating cellular environment. How these fluctuations from diverse origins functionally affect the precise cell fate decision making remains elusive. By taking a stochastic mathematical modeling approach, we unravel that the transcriptional variability arising within an NPC population due to intermittent cell cycle events significantly influences the neuron to NPC ratio during development. Our model proficiently quantifies the impact of different sources of heterogeneities in maintaining an exact neuron to NPC ratio and predicts plausible experimental ways to fine-tune the development of NPCs. In the future, these modeling insights may lead to better therapeutic avenues to regenerate neurons from NPCs.

Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors

Autism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causality and underlying molecular mechanisms linking ASH1L mutations to genesis of ASD/ID remain undetermined. Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes an ASD/ID mouse model revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.

Association Between Serum Insulin-Like Growth Factor 1 Levels and the Clinical Symptoms of Chronic Schizophrenia: Preliminary Findings.

Purpose: Insulin-like growth factor 1 (IGF-1) is a trophic mediator that is regulated by growth hormone and associated with the proliferation, development, and growth of neural cells. IGF-1 may be associated with the pathophysiology of schizophrenia, but this association remains controversial. This study aimed to investigate the relationship between serum IGF-1 levels and psychiatric symptoms in patients with chronic schizophrenia.Patients and Methods: A total of 65 patients were recruited from the University of Occupational and Environmental Health, Komine Eto Hospital, Moji Matsugae Hospital, Shin-Moji Hospital, and Tsutsumi Hospital in Kitakyushu between September 2019 and June 2020. Further, 20 healthy age- and sex-matched control participants were recruited from the Komine Eto Hospital and the University of Occupational and Environmental Health. Patients with schizophrenia were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Drug-Induced Extrapyramidal Symptoms Scale. Serum levels of free plus albumin-bound IGF-1 (IGF-1) were measured by immunoradiometric assay. The measurements were performed using antibody beads for bound/free separation. Associations between serum IGF-1 levels and the PANSS scores were determined. We also examined the associations between serum IGF-1 levels and diabetes, antipsychotic drug use, and disease duration.Results: No significant difference was found in the serum IGF-1 level between patients with schizophrenia and healthy controls. Serum IGF-1 levels were significantly negatively correlated with the PANSS total score (R2 = 0.06, p = 0.015) and PANSS general score (R2 = 0.088, p = 0.008), but not with the PANSS positive scores and PANSS negative scores. Serum IGF-1 levels were not related to the prevalence of diabetes (p = 0.64). However, a significant correlation was observed between serum IGF-1 levels and age (B = −1.88, p < 0.0001). Serum IGF-1 levels could not distinguish patients with schizophrenia and healthy controls.Conclusion: The association between serum IGF-1 levels and psychiatric symptoms may be complicated in patients with chronic schizophrenia.

The Dynamic Regulatory Role of miR-132 in Adult Hippocampal Neurogenesis and Neural Stem Cell Development

Introduction: Neurogenesis and neural stem cell development in the adult hippocampus remains an understudied and controversial area of research. These processes are known to be regulated by the dynamic interplay of transcription factors, cell-niche signalling, and recently, microRNAs. microRNA-132 (miR-132) is one example of a miRNA that offers critical insight into neurogenesis and neural stem cell development. The aim of this study was to systematically review the current literature regarding the role of miR-132-mediated post-transcriptional regulation of adult hippocampal neurogenesis (AHN) and neural stem cell (NSC) development. Methods: The literature search consisted of research articles found in PubMed, MEDLINE, Google Scholar, Cochrane, and Scopus databases using combinations of the Medical Subject Headings (MeSH) keywords “micro-RNA 132”, “miR-132”, “adult hippocampal neurogenesis”, and “neural stem cell development” to filter initial results. The study abstracted data in regards to the modalities of miR-132-mediated post-transcriptional regulation and the histophysiological implications associated with AHN and NSC development. Results: miR-132 has been implicated in mediating AHN as well as NSC differentiation and integration into the adult hippocampal dentate gyrus. Knockdown and overexpression of micro-RNA 132 in studies have demonstrated that miR-132 acts as a regulator of several downstream pathways and biochemical targets, including p250-GAP, methyl CpG-binding protein 2, AMPA glutamate receptors, and the RAS/MAPK axon signaling pathway. The fine-tuned modulation of neuronal plasticity associated with miR-132 suggests a role in higher level cognition, learning, and neurodegeneration within the context of Alzheimer’s disease. Discussion: The findings that miR-132 serves as a regulator of AHN and NSC development have significant clinical implications, specifically towards better understanding the pathological basis of neurodegenerative disorders as well as the development of novel miRNA-based therapeutics. Conclusion: The systematic review aggregated key findings on multiple potential biochemical targets and downstream feedback regulation pathways associated with miR-132 expression. Further research is needed to elucidate the mechanism of each pathway and the potential interplay between multiple proteins regulated by miR-132 that are associated with clinical disorders such as Alzheimer’s disease.

M6A Modifications Play Crucial Roles in Glial Cell Development and Brain Tumorigenesis.

RNA methylation is a reversible post-transcriptional modification to RNA and has a significant impact on numerous biological processes. N 6-methyladenosine (m6A) is known as one of the most common types of eukaryotic mRNA methylation modifications, and exists in a wide variety of organisms, including viruses, yeast, plants, mice, and humans. Widespread and dynamic m6A methylation is identified in distinct developmental stages in the brain, and controls development of neural stem cells and their differentiation into neurons, glial cells such as oligodendrocytes and astrocytes. Here we summarize recent advances in our understanding of RNA methylation regulation in brain development, neurogenesis, gliogenesis, and its dysregulation in brain tumors. This review will highlight biological roles of RNA methylation in development and function of neurons and glial cells, and provide insights into brain tumor formation, and diagnostic and treatment strategies.

The essential role of primary cilia in cerebral cortical development and disorders.

Primary cilium, first described in the 19th century in different cell types and organisms by Alexander Ecker, Albert Kolliker, Aleksandr Kowalevsky, Paul Langerhans, and Karl Zimmermann (Ecker, 1844; Kolliker, 1854; Kowalevsky, 1867; Langerhans, 1876; Zimmermann, 1898), play an essential modulatory role in diverse aspects of nervous system development and function. The primary cilium, sometimes referred to as the cell's 'antennae', can receive wide ranging inputs from cellular milieu, including morphogens, growth factors, neuromodulators, and neurotransmitters. Its unique structural and functional organization bequeaths it the capacity to hyper-concentrate signaling machinery in a restricted cellular domain approximately one-thousandth the volume of cell soma. Thus enabling it to act as a signaling hub that integrates diverse developmental and homestatic information from cellular milieu to regulate the development and function of neural cells. Dysfunction of primary cilia contributes to the pathophysiology of several brain malformations, intellectual disabilities, epilepsy, and psychiatric disorders. This review focuses on the most essential contributions of primary cilia to cerebral cortical development and function, in the context of neurodevelopmental disorders and malformations. It highlights the recent progress made in identifying the mechanisms underlying primary cilia's role in cortical progenitors, neurons and glia, in health and disease. A future challenge will be to translate these insights and advances into effective clinical treatments for ciliopathies.

Zika Virus Overview: Transmission, Origin, Pathogenesis, Animal Model and Diagnosis.

Zika virus (ZIKV) was first discovered in 1947 in Uganda. ZIKV did not entice much attention until Brazil hosted the 2016 Summer Olympics Game, where ZIKV attracted a global audience. ZIKV is a flavivirus that can be transmitted chiefly through the biting of the mosquito or sexually or by breastfeeding at a lower scale. As time passed, the recent discovery of how the ZIKV causes congenital neurodevelopmental defects, including microcephaly, makes us reevaluate the importance of ZIKV interaction with centrosome organization because centrosome plays an important role in cell division. When the ZIKV disrupts centrosome organization and mitotic abnormalities, this will alter neural progenitor differentiation. Altering the neural progenitor differentiation will lead to cell cycle arrest, increase apoptosis, and inhibit the neural progenitor cell differentiation, as this can lead to abnormalities in neural cell development resulting in microcephaly. Understanding the importance of ZIKV infection throughout the years, this review article gives an overview of the history, transmission routes, pathogenesis, animal models, and diagnosis.

Low Maternal Dietary Intake of Choline Regulates Toll-Like Receptor 4 Expression Via Histone H3K27me3 in Fetal Mouse Neural Progenitor Cells.

Choline is an essential nutrient and a primary dietary source of methyl groups that are vital for brain development. Low choline (LC) in the maternal diet during pregnancy alters neurogenesis in the fetal brain and leads to low cognitive performance. However, the key signaling pathways that are sensitive to maternal choline supply during neural progenitor cell (NPC) development and the epigenetic mechanisms by which choline availability regulates gene expression are unclear. Timed-pregnant Nestin-CFPnuc transgenic mice are fed either a control diet or LC diet during E11-17. Gene expression changes in sorted E17 NPCs are identified by RNA sequencing. A maternal LC diet significantly increases Tlr4 transcription, causing premature neuronal differentiation and enhanced ethanol-induced NLRP3 inflammasome activation. No changes in DNA methylation at the Tlr4 gene promoter region are detected; however, a 70% decrease in H3K27me3 is observed in the LC-treated NPCs. Inhibition of EZH2 decreases H3K27me3 levels and increases Tlr4 expression. Conversely, the application of catalytically inactive Cas9 with EZH2 to increase H3K27me3 at the Tlr4 promoter causes reduced Tlr4 expression. These data reveal an epigenetic mechanism for the effect of maternal choline availability on brain development, suggesting a likely intervention for neurodevelopmental diseases.

Exposure to bisphenol A differentially impacts neurodevelopment and behavior in Drosophila melanogaster from distinct genetic backgrounds

Bisphenol A (BPA) is a ubiquitous environmental chemical that has been linked to behavioral differences in children and shown to impact critical neurodevelopmental processes in animal models. Though data is emerging, we still have an incomplete picture of how BPA disrupts neurodevelopment; in particular, how its impacts may vary across different genetic backgrounds. Given the genetic tractability of Drosophila melanogaster, they present a valuable model to address this question. Fruit flies are increasingly being used for assessment of neurotoxicants because of their relatively simple brain structure and variety of measurable behaviors. Here we investigated the neurodevelopmental impacts of BPA across two genetic strains of Drosophila—w1118 (control) and the Fragile X Syndrome (FXS) model—by examining both behavioral and neuronal phenotypes. We show that BPA induces hyperactivity in larvae, increases repetitive grooming behavior in adults, reduces courtship behavior, impairs axon guidance in the mushroom body, and disrupts neural stem cell development in the w1118 genetic strain. Remarkably, for every behavioral and neuronal phenotype examined, the impact of BPA in FXS flies was either insignificant or contrasted with the phenotypes observed in the w1118 strain. This data indicates that the neurodevelopmental impacts of BPA can vary widely depending on genetic background and suggests BPA may elicit a gene-environment interaction with Drosophila fragile X mental retardation 1 (dFmr1)—the ortholog of human FMR1, which causes Fragile X Syndrome and is associated with autism spectrum disorder.

In Silico Identification of SOX1 Post-Translational Modifications Highlights a Shared Protein Motif.

The transcription factor SOX1 is a key regulator of neural stem cell development, acting to keep neural stem cells (NSCs) in an undifferentiated state. Postnatal expression of Sox1 is typically confined to the central nervous system (CNS), however, its expression in non-neural tissues has recently been implicated in tumorigenesis. The mechanism through which SOX1 may exert its function is not fully understood, and studies have mainly focused on changes in SOX1 expression at a transcriptional level, while its post-translational regulation remains undetermined. To investigate this, data were extracted from different publicly available databases and analysed to search for putative SOX1 post-translational modifications (PTMs). Results were compared to PTMs associated with SOX2 in order to identify potentially key PTM motifs common to these SOXB1 proteins, and mapped on SOX1 domain structural models. This approach identified several putative acetylation, phosphorylation, glycosylation and sumoylation sites within known functional domains of SOX1. In particular, a novel SOXB1 motif (xKSExSxxP) was identified within the SOX1 protein, which was also found in other unrelated proteins, most of which were transcription factors. These results also highlighted potential phospho-sumoyl switches within this SOXB1 motif identified in SOX1, which could regulate its transcriptional activity. This analysis indicates different types of PTMs within SOX1, which may influence its regulatory role as a transcription factor, by bringing changes to its DNA binding capacities and its interactions with partner proteins. These results provide new research avenues for future investigations on the mechanisms regulating SOX1 activity, which could inform its roles in the contexts of neural stem cell development and cancer.

Sequence heterochrony led to a gain of functionality in an immature stage of the central complex: A fly-beetle insight.

Animal behavior is guided by the brain. Therefore, adaptations of brain structure and function are essential for animal survival, and each species differs in such adaptations. The brain of one individual may even differ between life stages, for instance, as adaptation to the divergent needs of larval and adult life of holometabolous insects. All such differences emerge during development, but the cellular mechanisms behind the diversification of brains between taxa and life stages remain enigmatic. In this study, we investigated holometabolous insects in which larvae differ dramatically from the adult in both behavior and morphology. As a consequence, the central complex, mainly responsible for spatial orientation, is conserved between species at the adult stage but differs between larvae and adults of one species as well as between larvae of different taxa. We used genome editing and established transgenic lines to visualize cells expressing the conserved transcription factor retinal homeobox, thereby marking homologous genetic neural lineages in both the fly Drosophila melanogaster and the beetle Tribolium castaneum. This approach allowed us for the first time to compare the development of homologous neural cells between taxa from embryo to the adult. We found complex heterochronic changes including shifts of developmental events between embryonic and pupal stages. Further, we provide, to our knowledge, the first example of sequence heterochrony in brain development, where certain developmental steps changed their position within the ontogenetic progression. We show that through this sequence heterochrony, an immature developmental stage of the central complex gains functionality in Tribolium larvae.

A Polydopamine-Functionalized Carbon Microfibrous Scaffold Accelerates the Development of Neural Stem Cells.

Neuroregenerative medicine has witnessed impressive technological breakthroughs in recent years, but the currently available scaffold materials still have limitations regarding the development of effective treatment strategies for neurological diseases. Electrically conductive micropatterned materials have gained popularity in recent years due to their significant effects on neural stem cell fate. Polydopamine (PDA)—modified materials can also enhance the differentiation of neurons. In this work, we show that PDA-modified carbon microfiber skeleton composites have the appropriate conductivity, three-dimensional structure, and microenvironment regulation that are crucial for the growth of neural stem cells. The design we present is low-cost and easy to make and shows great promise for studying the growth and development of mouse neural stem cells. Our results show that the PDA-mediated formation of electrically conductive and viscous nanofiber webs promoted the adhesion, organization, and intercellular coupling of neural stem cells relative to the control group. PDA induced massive proliferation of neural stem cells and promoted the expression of Ki-67. Together, our results suggest that the composite material can be used as a multifunctional neural scaffold for clinical treatment and in vitro research by improving the structure, conductivity, and mechanical integrity of the regenerated tissues.