The existence of evolutionarily conserved regions in the vertebrate brain is well established. The rules and constraints underlying the evolution of neuron types, however, remain poorly understood. To compare neuron types across brain regions and species, we generated a cell type atlas of the brain of a bearded dragon and compared it with mouse datasets. Conserved classes of neurons could be identified from the expression of hundreds of genes, including homeodomain-type transcription factors and genes involved in connectivity. Within these classes, however, there are both conserved and divergent neuron types, precluding a simple categorization of the brain into ancestral and novel areas. In the thalamus, neuronal diversification correlates with the evolution of the cortex, suggesting that developmental origin and circuit allocation are drivers of neuronal identity and evolution. Description Lizard traces in the mouse brain Although lizards and mammals share common evolutionary roots, their pathways to today diverged hundreds of millions of years ago. Using single-cell transcriptomics, Hain et al. compared the brain of the lizard Pogona vitticeps, known as the Australian dragon, with that of the mouse (see the Perspective by Faltine-Gonzalez and Kebschull). They found that certain neuronal identities, marked by what transcription factors they express, are conserved from lizard to mammal, and others show evidence of evolutionary innovation. Therefore, the mammalian brain is an interwoven tapestry of new and ancestral traces. —PJH The mammalian and reptilian brains both result from parallel diversification processes from common ancestral neuron type families. INTRODUCTION Vertebrate evolution took an important turn before the onset of the Permian, 320 million years ago, with the transition of early tetrapods from water to land, the appearance of amniotes, and, soon thereafter, their bifurcation into sauropsids (future reptiles and birds) and synapsids (future mammals). Despite this branched history, the brains of all tetrapods share the same ancestral architecture defined by brain regions established during embryonic development (pallium, subpallium, thalamus, cerebellum, etc.) and by their long-range connections. Yet how variations on this common organization contributed to lineage- and species-specific adaptations is not clear. A commonly held assumption, for example, is that subcortical regions are ancient and “deeply conserved,” whereas the mammalian cortex is “new,” following profound changes in cortical development in this lineage. Brain regions, however, do not operate in isolation, raising the possibility that the evolution of interconnected neurons might be correlated. Likewise, areas in reptiles and mammals that derive from a common ancestral structure, such as the cerebral cortex, may have evolved in each lineage in such a way that they now each contain both ancient (thus common) and novel neuron types. Because traditional comparisons of developmental regions and projections may not suffice to reveal these similarities and differences, we investigated these issues using cellular transcriptomic approaches. RATIONALE Neurons are the most diverse cell types in the brain; their evolutionary diversification reflects changes in the developmental processes that produce them and, in turn, may drive changes in the neural circuits to which they belong. To the extent that a neuron’s transcriptome represents the molecular encoding of its identity, connectivity, and developmental and evolutionary histories, comparing neuronal transcriptomes across species should yield insights into brain evolution. To elucidate the evolution of neuronal diversity across brain regions, we generated a cell type atlas of the brain of a reptile, the Australian bearded dragon Pogona vitticeps, and compared it with existing mouse brain datasets. RESULTS We profiled 285,483 single-cell transcriptomes from the brain of Pogona and identified and annotated 233 distinct types of neurons. Computational integration of this dataset with publicly available mouse data revealed that lizard and mouse neurons co-cluster according to their regional and neurotransmitter identities. These integrated clusters expressed distinctive combinations of developmental transcription factors (including homeodomain-type) and genes involved in neuronal connectivity (cell junction, synaptic signaling, neuronal projections, synaptic transmission), indicating that both developmental origin and circuit allocation define broad, evolutionarily conserved classes of neurons in the amniote brain. At a finer level, these broad classes included neuron types with a wide range of transcriptomic variation across species. Certain neuron types could be readily mapped from lizard to mouse, indicating high transcriptomic similarity; others, however, could not be mapped across species unambiguously, owing to transcriptomic divergence. This dichotomy was true for all regions analyzed (telencephalon, diencephalon, and midbrain), indicating that neuronal diversification is ubiquitous in these brain regions. This was particularly evident in the thalamus, where neurons with high transcriptomic similarity across species (GABAergic reticular thalamic nucleus, glutamatergic “medial thalamus”) are juxtaposed with neuron types with diverging gene expression (glutamatergic “lateral thalamus”). In the lateral thalamus, lizard and mouse neurons from sensory relay nuclei did not co-cluster according to sensory modality, suggesting that these neurons may have diversified extensively, reflecting the different fates of their cortical partners in the reptilian and mammalian lineages. CONCLUSION Using comparative single-cell transcriptomics, we identified a core set of neuron types with high transcriptomic similarity between the brains of a lizard and a mammal, despite 320 million years of separate evolution. These neuron types are not restricted to subcortical regions but are found everywhere in the brain, including in the cerebral cortex, challenging the notion that certain brain regions are more ancient than others. Our data suggest that, even if the brain consists of developmental modules defined by ancient and shared molecular determinants, the evolution of the brain acts upon each module by keeping (e.g., reticular thalamic nucleus and medial thalamus) or diversifying (e.g., lateral thalamus) neuron types in a manner that is correlated with local and long-range connectivity. Transcriptomic study of neuronal evolution among amniotes. Reptiles and mammals evolved independently of each other for ~300 million years. We generated a cell type atlas from the brain of a lizard, Pogona vitticeps. Computational integration of these data with mouse transcriptomes reveals that telencephalon, diencephalon, and mesencephalon each contain mixtures of similar and divergent neurons, indicating that neuron diversification is ubiquitous in those regions.

Molecular diversity and evolution of neuron types in the amniote brain

Imagine a future viral pandemic where if you test positive for the new virus, you can quickly take some medicines at home for a few days so that you do not get too sick. To date, only single drugs have been approved for outpatient use against SARS-CoV-2, and we are learning that these have some limitations and may succumb to drug resistance. ABSTRACT Three directly acting antivirals (DAAs) demonstrated substantial reduction in COVID-19 hospitalizations and deaths in clinical trials. However, these agents did not completely prevent severe illness and are associated with cases of rebound illness and viral shedding. Combination regimens can enhance antiviral potency, reduce the emergence of drug-resistant variants, and lower the dose of each component in the combination. Concurrently targeting virus entry and virus replication offers opportunities to discover synergistic drug combinations. While combination antiviral drug treatments are standard for chronic RNA virus infections, no antiviral combination therapy has been approved for SARS-CoV-2. Here, we demonstrate that combining host-targeting antivirals (HTAs) that target TMPRSS2 and hence SARS-CoV-2 entry, with the DAA molnupiravir, which targets SARS-CoV-2 replication, synergistically suppresses SARS-CoV-2 infection in Calu-3 lung epithelial cells. Strong synergy was observed when molnupiravir, an oral drug, was combined with three TMPRSS2 (HTA) oral or inhaled inhibitors: camostat, avoralstat, or nafamostat. The combination of camostat plus molnupiravir was also effective against the beta and delta variants of concern. The pyrimidine biosynthesis inhibitor brequinar combined with molnupiravir also conferred robust synergistic inhibition. These HTA+DAA combinations had similar potency to the synergistic all-DAA combination of molnupiravir plus nirmatrelvir, the protease inhibitor found in paxlovid. Pharmacodynamic modeling allowed estimates of antiviral potency at all possible concentrations of each agent within plausible therapeutic ranges, suggesting possible in vivo efficacy. The triple combination of camostat, brequinar, and molnupiravir further increased antiviral potency. These findings support the development of HTA+DAA combinations for pandemic response and preparedness. IMPORTANCE Imagine a future viral pandemic where if you test positive for the new virus, you can quickly take some medicines at home for a few days so that you do not get too sick. To date, only single drugs have been approved for outpatient use against SARS-CoV-2, and we are learning that these have some limitations and may succumb to drug resistance. Here, we show that combinations of two oral drugs are better than the single ones in blocking SARS-CoV-2, and we use mathematical modeling to show that these drug combinations are likely to work in people. We also show that a combination of three oral drugs works even better at eradicating the virus. Our findings therefore bode well for the development of oral drug cocktails for at home use at the first sign of an infection by a coronavirus or other emerging viral pathogens.

Combinations of Host- and Virus-Targeting Antiviral Drugs Confer Synergistic Suppression of SARS-CoV-2

The corpus callosum is the largest white matter structure connecting the two cerebral hemispheres. Agenesis of the corpus callosum (ACC), complete or partial, is one of the most common cerebral malformations in humans with a reported incidence ranging between 1.8 per 10,000 livebirths to 230–600 per 10,000 in children and its presence is associated with neurodevelopmental disability. ACC may occur as an isolated anomaly or as a component of a complex disorder, caused by genetic changes, teratogenic exposures or vascular factors. Genetic causes are complex and include complete or partial chromosomal anomalies, autosomal dominant, autosomal recessive or X-linked monogenic disorders, which can be either de novo or inherited. The extreme genetic heterogeneity, illustrated by the large number of syndromes associated with ACC, highlight the underlying complexity of corpus callosum development. ACC is associated with a wide spectrum of clinical manifestations ranging from asymptomatic to neonatal death. The most common features are epilepsy, motor impairment and intellectual disability. The understanding of the genetic heterogeneity of ACC may be essential for the diagnosis, developing early intervention strategies, and informed family planning. This review summarizes our current understanding of the genetic heterogeneity in ACC and discusses latest discoveries.

https://www.frontiersin.org/articles/10.3389/fgene.2022.958570/pdf

Genetic heterogeneity in corpus callosum agenesis

Human pluripotent stem cell (hPSC)-derived retinal organoids are three-dimensional cellular aggregates that differentiate and self-organize to closely mimic the spatial and temporal patterning of the developing human retina. Retinal organoid models serve as reliable tools for studying human retinogenesis, yet limitations in the efficiency and reproducibility of current retinal organoid differentiation protocols have reduced the use of these models for more high-throughput applications such as disease modeling and drug screening. To address these shortcomings, the current study aimed to standardize prior differentiation protocols to yield a highly reproducible and efficient method for generating retinal organoids. Results demonstrated that through regulation of organoid size and shape using quick reaggregation methods, retinal organoids were highly reproducible compared to more traditional methods. Additionally, the timed activation of BMP signaling within developing cells generated pure populations of retinal organoids at 100% efficiency from multiple widely used cell lines, with the default forebrain fate resulting from the inhibition of BMP signaling. Furthermore, given the ability to direct retinal or forebrain fates at complete purity, mRNA-seq analyses were then utilized to identify some of the earliest transcriptional changes that occur during the specification of these two lineages from a common progenitor. These improved methods also yielded retinal organoids with expedited differentiation timelines when compared to traditional methods. Taken together, the results of this study demonstrate the development of a highly reproducible and minimally variable method for generating retinal organoids suitable for analyzing the earliest stages of human retinal cell fate specification. 

A highly reproducible and efficient method for retinal organoid differentiation from human pluripotent stem cells

Homeodomain transcription factors (HD TFs) are instrumental to vertebrate development. Mutations in HD TFs have been linked to human diseases, but their pathogenic mechanisms remain elusive. Here we use Cone-Rod Homeobox (CRX) as a model to decipher the disease-causing mechanisms of two HD mutations, p.E80A and p.K88N, that produce severe dominant retinopathies. Through integrated analysis of molecular and functional evidence in vitro and in knock-in mouse models, we uncover two novel gain-of-function mechanisms: p.E80A increases CRX-mediated transactivation of canonical CRX target genes in developing photoreceptors; p.K88N alters CRX DNA-binding specificity resulting in binding at ectopic sites and severe perturbation of CRX target gene expression. Both mechanisms produce novel retinal morphological defects and hinder photoreceptor maturation distinct from loss-of-function models. This study reveals the distinct roles of E80 and K88 residues in CRX HD regulatory functions and emphasizes the importance of transcriptional precision in normal development. 

Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms

Forebrain development in vertebrates is regulated by transcription factors encoded by homeobox, bHLH and forkhead gene families throughout the progressive and overlapping stages of neural induction and patterning, regional specification and generation of neurons and glia from central nervous system (CNS) progenitor cells. Moreover, cell fate decisions, differentiation and migration of these committed CNS progenitors are controlled by the gene regulatory networks that are regulated by various homeodomain-containing transcription factors, including but not limited to those of the Pax (paired), Nkx, Otx (orthodenticle), Gsx/Gsh (genetic screened), and Dlx (distal-less) homeobox gene families. This comprehensive review outlines the integral role of key homeobox transcription factors and their target genes on forebrain development, focused primarily on the telencephalon. Furthermore, links of these transcription factors to human diseases, such as neurodevelopmental disorders and brain tumors are provided.

/pdf/genetic-regulation-of-vertebrate-forebrain-development-by-7fpj2c9t.pdf

Genetic Regulation of Vertebrate Forebrain Development by Homeobox Genes

Influenza viruses cause significant morbidity and mortality worldwide but can be treated with antiviral drugs. In 2018, a highly effective antiviral drug, baloxavir marboxil, was licensed. ABSTRACT Amino acid substitutions I38T and E23K in the influenza polymerase acidic (PA) protein lead to reduced susceptibility to the influenza antiviral drug baloxavir. The in vivo effectiveness of baloxavir and oseltamivir for treatment of these viruses is currently unknown. Using patient-derived influenza isolates, combination therapy was equally effective as monotherapy in reducing viral titers in the upper respiratory tract of ferrets infected with A(H1N1pdm09)-PA/E23K or A(H3N2)-PA/I38T. When treated with baloxavir plus oseltamivir, infection with a mixture of PA/I38T or PA/E23K and corresponding wild-type virus was characterized by a lower selection of viruses with reduced baloxavir susceptibility over the course of infection compared to baloxavir monotherapy. De novo emergence of the oseltamivir resistance mutation NA/H275Y occurred in ferrets treated with oseltamivir alone but not in ferrets treated with baloxavir plus oseltamivir. Our data suggest that combination therapy with influenza drugs with different mechanisms of action decreased the selection pressure for viruses with reduced drug susceptibility. IMPORTANCE Influenza viruses cause significant morbidity and mortality worldwide but can be treated with antiviral drugs. In 2018, a highly effective antiviral drug, baloxavir marboxil, was licensed. However, the selection of viruses with baloxavir resistance was relatively high following treatment, which may compromise the effectiveness of the drug. Here, we took two different influenza viruses that are resistant to baloxavir and tested the effectiveness alone and in combination with oseltamivir (a second influenza antiviral drug) in the ferret model. Our findings suggest that combination treatment may be a more effective method than monotherapy to reduce the selection of resistant viruses. These results may have important clinical implications for the treatment of influenza.

Effect of Baloxavir and Oseltamivir in Combination on Infection with Influenza Viruses with PA/I38T or PA/E23K Substitutions in the Ferret Model

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Ankita M. George

Author Tools

Chat about Author

Papers

Genetic Regulation of Vertebrate Forebrain Development by Homeobox Genes

Effect of Baloxavir and Oseltamivir in Combination on Infection with Influenza Viruses with PA/I38T or PA/E23K Substitutions in the Ferret Model