{"title":"Beyond the Rainbow: A Review of Advanced Lineage Tracing Methodologies for Interrogating the Initiation, Evolution, and Recurrence of Brain Tumors","authors":"Sara Sabet, Joshua J. Breunig","doi":"10.1159/000530329","DOIUrl":"https://doi.org/10.1159/000530329","url":null,"abstract":"The mammalian forebrain is perhaps the pinnacle of evolution and one of the most complex structures in known existence. The origin of this complexity and diversity partly lies in dynamic behavior of progenitors during embryonic neural development, all of which is under the control of regulatory mechanisms that ensure all the elements end up in the right place at the right time. Historically, dye-base, histochemical, enzymatic, or fluorescent lineage tracing techniques have been used deconvolute developmental dynamics in tissues and cells. Technical limitations resulted from a restrictive number of fluorophores, the half-life of the dyes, or the ability to deconvolute mixed population. These limitations often impede larger scale lineage tracing using these methods in spatial and temporal contexts. Genetic barcoding techniques have been used for decades to explore clonal investigations and have now evolved with high-throughput sequencing methods to allow for impressive insights into population and even organism-level lineage relationships. In this review, we will discuss the progression of lineage tracing methodologies and how they are applied to answer questions around molecular and cellular mechanisms of gliogenesis and neurogenesis. We will also discuss recent advances in computational biology, single-cell sequencing, and in situ-based lineage tracing methodologies. Incorporation of these methods into toolset of lineage tracing promise to enable a higher resolution, multimodal view of neural lineages during development and disease processes that highjack developmental signaling such as brain tumor development and recurrence – where traditional developmental hierarchies become more plastic and less predictable. Given the dismal prognosis of high-grade brain tumors like glioblastoma multiforme, a better understanding of the lineage relationships leading to disease heterogeneity and recurrence is desperately needed to formulate efficacious approaches to treatment. Here we discuss a historical foundation on, as well as the future of, lineage tracing at the intersection of development and disease.","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":"45 1","pages":"181 - 190"},"PeriodicalIF":2.9,"publicationDate":"2023-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49022988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marie Sasaki, T. Mitsuhashi, Fumiko Goto, S. Shibata, K. Kubo, Shinju Oku, Akihiro Owashi, Takao Takahashi
{"title":"Maternal Immune Activation by Polyinosinic-Polycytidylic Acid Exposure Causes Cerebral Cortical Dysgenesis through Dysregulated Cell Cycle Kinetics of Neural Stem/Progenitor Cells","authors":"Marie Sasaki, T. Mitsuhashi, Fumiko Goto, S. Shibata, K. Kubo, Shinju Oku, Akihiro Owashi, Takao Takahashi","doi":"10.1159/000529317","DOIUrl":"https://doi.org/10.1159/000529317","url":null,"abstract":"Maternal immune activation reportedly causes dysregulation of the cell cycle in stem cells and impairment of higher cortical function in rodents. Furthermore, in humans, maternal immune activation during the first to second trimester of pregnancy is strongly correlated with increased incidence of autism spectrum disorder in the offspring. Here, we show that in utero exposure to polyinosinic-polycytidylic acid (poly (I:C)) in mice during the early phase of neuronogenesis increases the probability of differentiation (quiescent fraction [Q fraction]) of neural stem/progenitor cells (NSPCs) without change in the length of cell cycle. This abnormal increase in the Q fraction is assumed to reduce the peak population size of NSPCs, resulting in the thinning of the neocortex in offspring because of the reduced production of neurons. Furthermore, the neocortex of poly (I:C)-exposed mice does not exhibit a layer-specific reduction in radial thickness, possibly because of increased apoptosis caused by poly (I:C) exposure during all stages of cortical development. These results suggest that maternal immune activation by poly (I:C) exposure may affect neocortical histogenesis by altering the cell cycle kinetics of NSPCs. In addition, the timing and amount of poly (I:C) exposure during pregnancy may have profound effects on cerebral cortical histogenesis.","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":"45 1","pages":"115 - 125"},"PeriodicalIF":2.9,"publicationDate":"2023-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47507709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Humberto de Oliveira Simões, Eduardo Tanaka Massuda, Erikson Felipe Furtado, Sthella Zanchetta
{"title":"Auditory Outcomes in Adolescents with Prenatal Alcohol Exposure.","authors":"Humberto de Oliveira Simões, Eduardo Tanaka Massuda, Erikson Felipe Furtado, Sthella Zanchetta","doi":"10.1159/000528846","DOIUrl":"https://doi.org/10.1159/000528846","url":null,"abstract":"<p><p>The aim of the study was to investigate three aspects of auditory function (auditory acuity, cochlear dysfunction, and auditory processing) in adolescents with fetal alcohol exposure without phenotypic changes. Fifty-one adolescents with and without intrauterine exposure to alcohol were selected from a cohort study. The summons, evaluation, and analysis of the results were carried out blindly regarding the respective exposure to alcohol. The auditory tests were pure-tone audiometry, transient otoacoustic emissions, and behavioral assessment of auditory processing (speech-in-noise, dichotic digits, and gap-in-noise). After testing, 45 adolescents were included in the evaluation and were divided into exposed (n = 22) and non-exposed (n = 23) groups. Hearing loss was identified in one subject in the exposed group (4.5%). In the absence of hearing loss, there were no significant differences in tonal thresholds or in the magnitudes of the sensory (cochlear) responses between groups (p > 0.05). There was also no difference between the two groups regarding performance on the processing tests (speech-in-noise p = 0.71, dichotic p = 0.94, and gap-in-noise p = 0.33). However, the exposed group had more cases of hearing disorders (hearing loss plus auditory processing disorders) than the non-exposed group (22.7% vs. 4.3%).</p>","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":"45 1","pages":"27-36"},"PeriodicalIF":2.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10129020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9678251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Alterations in the Proteome of Developing Neocortical Synaptosomes in the Absence of MET Signaling Revealed by Comparative Proteomics.","authors":"Kathie L Eagleson, Pat Levitt","doi":"10.1159/000529981","DOIUrl":"10.1159/000529981","url":null,"abstract":"<p><p>Alterations in the expression of genes encoding proteins involved in synapse formation, maturation, and function are a hallmark of many neurodevelopmental and psychiatric disorders. For example, there is reduced neocortical expression of the MET receptor tyrosine kinase (MET) transcript and protein in Autism Spectrum Disorder (ASD) and Rett syndrome. Preclinical in vivo and in vitro models manipulating MET signaling reveal that the receptor modulates excitatory synapse development and maturation in select forebrain circuits. The molecular adaptations underlying the altered synaptic development remain unknown. We performed a comparative mass spectrometry analysis of synaptosomes generated from the neocortex of wild type and Met null mice during the peak of synaptogenesis (postnatal day 14; data are available from ProteomeXchange with identifier PXD033204). The analyses revealed broad disruption of the developing synaptic proteome in the absence of MET, consistent with the localization of MET protein in pre- and postsynaptic compartments, including proteins associated with the neocortical synaptic MET interactome and those encoded by syndromic and ASD risk genes. In addition to an overrepresentation of altered proteins associated with the SNARE complex, multiple proteins in the ubiquitin-proteasome system and associated with the synaptic vesicle, as well as proteins that regulate actin filament organization and synaptic vesicle exocytosis/endocytosis, were disrupted. Taken together, the proteomic changes are consistent with structural and functional changes observed following alterations in MET signaling. We hypothesize that the molecular adaptations following Met deletion may reflect a general mechanism that produces circuit-specific molecular changes due to loss or reduction of synaptic signaling proteins.</p>","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":"45 3","pages":"126-138"},"PeriodicalIF":2.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10239366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9728335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Association of Nogo-A Gene Polymorphisms with Cerebral Palsy in Southern China: A Case-Control Study.","authors":"Yuxin Wang, Lu He, Jingyu Huang, Jinling Li, Liru Liu, Yunxian Xu, Tingting Peng, Xubo Yang, Yiting Zhao, Chaoqiong Fu, Shiya Huang, Hongmei Tang, Kaishou Xu","doi":"10.1159/000527801","DOIUrl":"https://doi.org/10.1159/000527801","url":null,"abstract":"<p><p>Cerebral palsy (CP) is a motor and postural disorder syndrome caused by the nonprogressive dysfunction of the developing brain. Previous studies strongly indicated that the Nogo-A gene might be related to the pathogenesis of CP. The objective of this research was to explore the relationship between Nogo-A polymorphisms (rs1012603, rs12464595, and rs2864052) and CP in Southern China. The Hardy-Weinberg equilibrium (HWE) testing, allele and genotype frequencies analysis, and haplotype association analysis were applied to the genotyping of 592 CP children and 600 controls. The results showed that the allele and genotype frequencies of rs1012603 of CP group were significantly different from the control group. The haplotype \"TTGGG\" was significantly associated with an increased risk of CP. The allele frequencies of rs1012603 were significant differences between CP with spastic diplegia, female CP cases, and controls. Furthermore, significant differences in allele and genotype frequencies were also noticed between GMFCS I of CP and controls for rs1012603, and significant differences in allele and genotype frequencies were observed between the ADL (>9) of CP and controls for rs1012603 and rs12464595. This study showed that the SNPs rs1012603 of Nogo-A were significantly correlated with CP, and the correlations were also found in spastic diplegia, GMFCS I of CP, ADL (>9) of CP, and female subgroups, indicating that Nogo-A might mainly affect mild types of CP and there might be sex-related differences.</p>","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":"45 1","pages":"8-18"},"PeriodicalIF":2.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10129029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9666155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Danielle Guez-Barber, Amelia J Eisch, Ana G Cristancho
{"title":"Developmental Brain Injury and Social Determinants of Health: Opportunities to Combine Preclinical Models for Mechanistic Insights into Recovery.","authors":"Danielle Guez-Barber, Amelia J Eisch, Ana G Cristancho","doi":"10.1159/000530745","DOIUrl":"10.1159/000530745","url":null,"abstract":"<p><p>Epidemiological studies show that social determinants of health are among the strongest factors associated with developmental outcomes after prenatal and perinatal brain injuries, even when controlling for the severity of the initial injury. Elevated socioeconomic status and a higher level of parental education correlate with improved neurologic function after premature birth. Conversely, children experiencing early life adversity have worse outcomes after developmental brain injuries. Animal models have provided vital insight into mechanisms perturbed by developmental brain injuries, which have indicated directions for novel therapeutics or interventions. Animal models have also been used to learn how social environments affect brain maturation through enriched environments and early adverse conditions. We recognize animal models cannot fully recapitulate human social circumstances. However, we posit that mechanistic studies combining models of developmental brain injuries and early life social environments will provide insight into pathways important for recovery. Some studies combining enriched environments with neonatal hypoxic injury models have shown improvements in developmental outcomes, but further studies are needed to understand the mechanisms underlying these improvements. By contrast, there have been more limited studies of the effects of adverse conditions on developmental brain injury extent and recovery. Uncovering the biological underpinnings for early life social experiences has translational relevance, enabling the development of novel strategies to improve outcomes through lifelong treatment. With the emergence of new technologies to analyze subtle molecular and behavioral phenotypes, here we discuss the opportunities for combining animal models of developmental brain injury with social construct models to deconvolute the complex interactions between injury, recovery, and social inequity.</p>","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":" ","pages":"255-267"},"PeriodicalIF":2.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9422748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Arthritis in Children with Psychiatric Deteriorations: A Case Series.","authors":"Meiqian Ma, Jesse Sandberg, Bahare Farhadian, Melissa Silverman, Yuhuan Xie, Margo Thienemann, Jennifer Frankovich","doi":"10.1159/000530854","DOIUrl":"10.1159/000530854","url":null,"abstract":"<p><p>Pediatric acute-onset neuropsychiatric syndrome (PANS), pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections, Sydenham chorea, and other postinfectious psychiatric deteriorations are thought to be caused by inflammatory/autoimmune mechanisms, likely involving the basal ganglia based on imaging studies. Patients have a relapsing-remitting course and some develop severe refractory psychiatric disease. We found that 55/193 (28%) of consecutive patients meeting PANS criteria developed chronic arthritis and 25/121 (21%) of those with related psychiatric deteriorations developed chronic arthritis. Here we describe 7 of these patients in detail and one sibling. Many of our patients often have \"dry\" arthritis (no effusions found on physical exam) but subtle effusions detected by imaging and features of spondyloarthritis, enthesitis, and synovitis. Joint capsule thickening, not previously reported in children, is a common finding in the presented cases and in psoriatic arthritis in adults. Due to the severity of psychiatric symptoms in some cases, which often overshadow joint symptoms, and concomitant sensory dysregulation (making the physical exam unreliable in the absence of effusions), we rely on imaging to improve sensitivity and specificity of the arthritis classification. We also report the immunomodulatory treatments of these 7 patients (initially nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs with escalation to biologic medications) and note any coincidental changes to their arthritis and psychiatric symptoms while on immunomodulation. Patients with overlapping psychiatric syndromes and arthritis may have a unifying cause and pose unique challenges; a multi-disciplinary team can utilize imaging to tailor and coordinate treatment for this patient population.</p>","PeriodicalId":50585,"journal":{"name":"Developmental Neuroscience","volume":" ","pages":"325-334"},"PeriodicalIF":2.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9515126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}