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Birth Defects Research Nov 2019Neural tube defects (NTDs) are the second most common congenital malformations in humans affecting the development of the central nervous system. Although NTD... (Review)
Review
Neural tube defects (NTDs) are the second most common congenital malformations in humans affecting the development of the central nervous system. Although NTD pathogenesis has not yet been fully elucidated, many risk factors, both genetic and environmental, have been extensively reported. Classically divided in two main sub-groups (open and closed defects) NTDs present extremely variable prognosis mainly depending on the site of the lesion. Herein, we review the literature on the histological and pathological features, epidemiology, prenatal diagnosis, and prognosis, based on the type of defect, with the aim of providing important information based on NTDs classification for clinicians and scientists.
Topics: Anencephaly; Female; Humans; Neural Tube Defects; Pregnancy; Prenatal Diagnosis; Risk Factors
PubMed: 30421543
DOI: 10.1002/bdr2.1380 -
Development (Cambridge, England) Feb 2017Neural tube closure has been studied for many decades, across a range of vertebrates, as a paradigm of embryonic morphogenesis. Neurulation is of particular interest in... (Review)
Review
Neural tube closure has been studied for many decades, across a range of vertebrates, as a paradigm of embryonic morphogenesis. Neurulation is of particular interest in view of the severe congenital malformations - 'neural tube defects' - that result when closure fails. The process of neural tube closure is complex and involves cellular events such as convergent extension, apical constriction and interkinetic nuclear migration, as well as precise molecular control via the non-canonical Wnt/planar cell polarity pathway, Shh/BMP signalling, and the transcription factors Grhl2/3, Pax3, Cdx2 and Zic2. More recently, biomechanical inputs into neural tube morphogenesis have also been identified. Here, we review these cellular, molecular and biomechanical mechanisms involved in neural tube closure, based on studies of various vertebrate species, focusing on the most recent advances in the field.
Topics: Animals; Body Patterning; Cell Movement; Cell Polarity; Embryonic Development; Fibronectins; Humans; Laminin; Morphogenesis; Neural Tube; Neural Tube Defects; Neurulation; Proteoglycans; Risk Factors; Signal Transduction; Stress, Mechanical; Transcription Factors
PubMed: 28196803
DOI: 10.1242/dev.145904 -
Nature Oct 2022Embryonic stem (ES) cells can undergo many aspects of mammalian embryogenesis in vitro, but their developmental potential is substantially extended by interactions with...
Embryonic stem (ES) cells can undergo many aspects of mammalian embryogenesis in vitro, but their developmental potential is substantially extended by interactions with extraembryonic stem cells, including trophoblast stem (TS) cells, extraembryonic endoderm stem (XEN) cells and inducible XEN (iXEN) cells. Here we assembled stem cell-derived embryos in vitro from mouse ES cells, TS cells and iXEN cells and showed that they recapitulate the development of whole natural mouse embryo in utero up to day 8.5 post-fertilization. Our embryo model displays headfolds with defined forebrain and midbrain regions and develops a beating heart-like structure, a trunk comprising a neural tube and somites, a tail bud containing neuromesodermal progenitors, a gut tube, and primordial germ cells. This complete embryo model develops within an extraembryonic yolk sac that initiates blood island development. Notably, we demonstrate that the neurulating embryo model assembled from Pax6-knockout ES cells aggregated with wild-type TS cells and iXEN cells recapitulates the ventral domain expansion of the neural tube that occurs in natural, ubiquitous Pax6-knockout embryos. Thus, these complete embryoids are a powerful in vitro model for dissecting the roles of diverse cell lineages and genes in development. Our results demonstrate the self-organization ability of ES cells and two types of extraembryonic stem cells to reconstitute mammalian development through and beyond gastrulation to neurulation and early organogenesis.
Topics: Animals; Cell Lineage; Embryo, Mammalian; Embryonic Stem Cells; Endoderm; Gastrulation; Heart; Mesencephalon; Mice; Models, Biological; Neural Tube; Neurulation; Organogenesis; PAX6 Transcription Factor; Prosencephalon; Somites
PubMed: 36007540
DOI: 10.1038/s41586-022-05246-3 -
Trends in Neurosciences Jul 2020Neural tube defects (NTDs) represent a failure of the neural plate to complete the developmental transition to a neural tube. NTDs are the most common birth anomaly of... (Review)
Review
Neural tube defects (NTDs) represent a failure of the neural plate to complete the developmental transition to a neural tube. NTDs are the most common birth anomaly of the CNS. Following mandatory folic acid fortification of dietary grains, a dramatic reduction in the incidence of NTDs was observed in areas where the policy was implemented, yet the genetic drivers of NTDs in humans, and the mechanisms by which folic acid prevents disease, remain disputed. Here, we discuss current understanding of human NTD genetics, recent advances regarding potential mechanisms by which folic acid might modify risk through effects on the epigenome and transcriptome, and new approaches to study refined phenotypes for a greater appreciation of the developmental and genetic causes of NTDs.
Topics: Folic Acid; Humans; Neural Tube Defects
PubMed: 32423763
DOI: 10.1016/j.tins.2020.04.009 -
Nature Nov 2021Understanding human organ formation is a scientific challenge with far-reaching medical implications. Three-dimensional stem-cell cultures have provided insights into...
Understanding human organ formation is a scientific challenge with far-reaching medical implications. Three-dimensional stem-cell cultures have provided insights into human cell differentiation. However, current approaches use scaffold-free stem-cell aggregates, which develop non-reproducible tissue shapes and variable cell-fate patterns. This limits their capacity to recapitulate organ formation. Here we present a chip-based culture system that enables self-organization of micropatterned stem cells into precise three-dimensional cell-fate patterns and organ shapes. We use this system to recreate neural tube folding from human stem cells in a dish. Upon neural induction, neural ectoderm folds into a millimetre-long neural tube covered with non-neural ectoderm. Folding occurs at 90% fidelity, and anatomically resembles the developing human neural tube. We find that neural and non-neural ectoderm are necessary and sufficient for folding morphogenesis. We identify two mechanisms drive folding: (1) apical contraction of neural ectoderm, and (2) basal adhesion mediated via extracellular matrix synthesis by non-neural ectoderm. Targeting these two mechanisms using drugs leads to morphological defects similar to neural tube defects. Finally, we show that neural tissue width determines neural tube shape, suggesting that morphology along the anterior-posterior axis depends on neural ectoderm geometry in addition to molecular gradients. Our approach provides a new route to the study of human organ morphogenesis in health and disease.
Topics: Ectoderm; Humans; Models, Biological; Morphogenesis; Neural Plate; Neural Tube; Neural Tube Defects; Organ Culture Techniques; Regeneration; Stem Cells
PubMed: 34707290
DOI: 10.1038/s41586-021-04026-9 -
Nature Dec 2022Our understanding of human early development is severely hampered by limited access to embryonic tissues. Due to their close evolutionary relationship with humans,...
Our understanding of human early development is severely hampered by limited access to embryonic tissues. Due to their close evolutionary relationship with humans, nonhuman primates are often used as surrogates to understand human development but currently suffer from a lack of in vivo datasets, especially from gastrulation to early organogenesis during which the major embryonic cell types are dynamically specified. To fill this gap, we collected six Carnegie stage 8-11 cynomolgus monkey (Macaca fascicularis) embryos and performed in-depth transcriptomic analyses of 56,636 single cells. Our analyses show transcriptomic features of major perigastrulation cell types, which help shed light on morphogenetic events including primitive streak development, somitogenesis, gut tube formation, neural tube patterning and neural crest differentiation in primates. In addition, comparative analyses with mouse embryos and human embryoids uncovered conserved and divergent features of perigastrulation development across species-for example, species-specific dependency on Hippo signalling during presomitic mesoderm differentiation-and provide an initial assessment of relevant stem cell models of human early organogenesis. This comprehensive single-cell transcriptome atlas not only fills the knowledge gap in the nonhuman primate research field but also serves as an invaluable resource for understanding human embryogenesis and developmental disorders.
Topics: Animals; Humans; Mice; Gastrulation; Macaca fascicularis; Organogenesis; Single-Cell Analysis; Embryoid Bodies; Gene Expression Profiling; Primitive Streak; Neural Tube; Neural Crest; Hippo Signaling Pathway; Mesoderm; Stem Cells
PubMed: 36517595
DOI: 10.1038/s41586-022-05526-y -
Development (Cambridge, England) Aug 2021The spinal cord receives input from peripheral sensory neurons and controls motor output by regulating muscle innervating motor neurons. These functions are carried out...
The spinal cord receives input from peripheral sensory neurons and controls motor output by regulating muscle innervating motor neurons. These functions are carried out by neural circuits comprising molecularly distinct neuronal subtypes generated in a characteristic spatiotemporal arrangement from progenitors in the embryonic neural tube. To gain insight into the diversity and complexity of cells in the developing human neural tube, we used single-cell mRNA sequencing to profile cervical and thoracic regions in four human embryos of Carnegie stages (CS) CS12, CS14, CS17 and CS19 from gestational weeks 4-7. Analysis of progenitor and neuronal populations from the neural tube and dorsal root ganglia identified dozens of distinct cell types and facilitated the reconstruction of the differentiation pathways of specific neuronal subtypes. Comparison with mouse revealed overall similarity of mammalian neural tube development while highlighting some human-specific features. These data provide a catalogue of gene expression and cell type identity in the human neural tube that will support future studies of sensory and motor control systems. The data can be explored at https://shiny.crick.ac.uk/scviewer/neuraltube/.
Topics: Animals; Cell Differentiation; Embryo, Mammalian; Ganglia, Spinal; Gene Expression; Gene Expression Profiling; Humans; Mice; Motor Neurons; Neural Tube; Sensory Receptor Cells; Spinal Cord; Thorax; Transcriptome
PubMed: 34351410
DOI: 10.1242/dev.199711 -
Development (Cambridge, England) Mar 2019The coordinated spatial and temporal regulation of gene expression in the vertebrate neural tube determines the identity of neural progenitors and the function and...
The coordinated spatial and temporal regulation of gene expression in the vertebrate neural tube determines the identity of neural progenitors and the function and physiology of the neurons they generate. Progress has been made deciphering the gene regulatory programmes that are responsible for this process; however, the complexity of the tissue has hampered the systematic analysis of the network and the underlying mechanisms. To address this, we used single cell mRNA sequencing to profile cervical and thoracic regions of the developing mouse neural tube between embryonic days 9.5-13.5. We confirmed that the data accurately recapitulates neural tube development, allowing us to identify new markers for specific progenitor and neuronal populations. In addition, the analysis highlighted a previously underappreciated temporal component to the mechanisms that generate neuronal diversity, and revealed common features in the sequence of transcriptional events that lead to the differentiation of specific neuronal subtypes. Together, the data offer insight into the mechanisms that are responsible for neuronal specification and provide a compendium of gene expression for classifying spinal cord cell types that will support future studies of neural tube development, function and disease.
Topics: Animals; Cell Differentiation; Cluster Analysis; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Interneurons; Male; Mice; Neural Tube; Neurons; Organogenesis; RNA, Messenger; Single-Cell Analysis; Spinal Cord; Time Factors; Transcription Factors; Transcriptome
PubMed: 30846445
DOI: 10.1242/dev.173807