scholarly journals Coexpression enables multi-study cellular trajectories of development and disease

2019 ◽  
Author(s):  
Brian Hie ◽  
Hyunghoon Cho ◽  
Bryan Bryson ◽  
Bonnie Berger
Keyword(s):  
Neuronal Development ◽  
Developmental Stages ◽  
Biological Variation ◽  
Specific Information ◽  
Disease Pathogenesis ◽  
Technical Bias ◽  
Cellular Development ◽  
Microglial Response ◽  
Myelin Injury ◽  
Transcriptomic Studies

AbstractSingle-cell transcriptomic studies of diverse and complex systems are becoming ubiquitous. Algorithms now attempt to integrate patterns across these studies by removing all study-specific information, without distinguishing unwanted technical bias from relevant biological variation. Integration remains difficult when capturing biological variation that is distributed across studies, as when combining disparate temporal snapshots into a panoramic, multi-study trajectory of cellular development. Here, we show that a fundamental analytic shift to gene coexpression within clusters of cells, rather than gene expression within individual cells, balances robustness to bias with preservation of meaningful inter-study differences. We leverage this insight in Trajectorama, an algorithm which we use to unify trajectories of neuronal development and hematopoiesis across studies that each profile separate developmental stages, a highly challenging task for existing methods. Trajectorama also reveals systems-level processes relevant to disease pathogenesis within the microglial response to myelin injury. Trajectorama benefits from efficiency and scalability, processing nearly one million cells in around an hour.

scholarly journals From Zero to Neuro-Reprogramming: Innovations in Translational Neuroregenerative Medicine

2019 ◽  
Vol 9 (1) ◽  
pp. 54-60
Author(s):  
Ahmad Galuta ◽  
Eve Tsai
Keyword(s):  
Stem Cells ◽  
Nervous System ◽  
Large Scale ◽  
Neuronal Development ◽  
Developmental Stages ◽  
Study Patient ◽  
Patient Specific ◽  
Translational Study ◽  
Neuroregenerative Medicine

Acquiring live human nervous tissue for research presents ethical and technical constraints. As a result, clinicians and scientists resort to using animal models to investigate human neuronal development and degeneration. However, innate species differences in neurobiology have hindered the translation of disease pathologies and development of therapeutic strategies. The discovery of endogenous neural stem cells (NSCs) and their examination has been critical for neuronal development, degeneration and regeneration. NSCs can exist in different developmental stages, embryonic through adult, and possess the capacity to generate the various cells that make up the nervous system. Importantly, human somatic cells can be obtained non-invasively and genetically reprogrammed into NSCs providing an ethically viable source of stem cells for translational study and potential therapy. Novel methods to generate NSCs of various developmental origins and regional identities are rapidly evolving to provide safer, quicker, and more efficient reprogramming strategies. Reprogrammed NSCs share many molecular and functional attributes with their endogenous NSC counterparts and can be used for in vitro modelling at a large scale. The accessibility to study patient specific NSCs allows the causal inferences of human disease mechanisms that may be unfeasible to model in animals. Despite the novelty of this burgeoning field, the opportunity for translational discoveries in neuronal development and degeneration and for therapeutic applications is unprecedented. This review will highlight the advances in manufacturing NSCs and their translational implications for disease modelling and potential treatment of the nervous system.

scholarly journals Quantitative proteomic alterations of human iPSC-based neuronal development indicate early onset of Rett syndrome

2019 ◽  
Author(s):  
Suzy Varderidou-Minasian ◽  
Lisa Hinz ◽  
Dominique Hagemans ◽  
Danielle Posthuma ◽  
Maarten Altelaar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Rett Syndrome ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Developmental Stages ◽  
Expression Profiles ◽  
Induced Pluripotent Stem Cell ◽  
Gene Encoding ◽  
Neurodevelopmental Disease ◽  
New Biomarkers

AbstractRett syndrome (RTT) is a progressive neurodevelopmental disease often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanisms by which impaired MeCP2 induces the pathological abnormalities in the brain are not understood. To understand the molecular mechanisms involved in disease, we used an RTT patient induced pluripotent stem cell (iPSC)-based model and applied an in-depth high-resolution quantitative mass spectrometry-based analysis during early stages of neuronal development. Our data provide evidence of proteomic alteration at developmental stages long before the phase that symptoms of RTT syndrome become apparent. Differences in expression profiles became more pronounced from early to late neural stem cell phases, although proteins involved in immunity, metabolic processes and calcium signaling were already affected at initial stages. These results can help development of new biomarkers and therapeutic approaches by selectively target the affected proteins in RTT syndrome.

scholarly journals BDNF-dependent modulation of axonal transport is selectively impaired in ALS

2021 ◽  
Author(s):  
Andrew P. Tosolini ◽  
James N. Sleigh ◽  
Sunaina Surana ◽  
Elena R. Rhymes ◽  
Stephen D. Cahalan ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Axonal Transport ◽  
Neuronal Development ◽  
Therapeutic Interventions ◽  
Wild Type ◽  
Disease Pathogenesis ◽  
Sciatic Nerves ◽  
Lateral Sclerosis ◽  
Selective Impairment ◽  
Stimulation Of

AbstractAxonal transport ensures long-range delivery of essential cargoes between proximal and distal compartments of neurons, and is needed for neuronal development, function, and survival. Deficits in axonal transport have been detected at pre-symptomatic stages in mouse models of amyotrophic lateral sclerosis (ALS), suggesting that impairments are fundamental for disease pathogenesis. However, the precise mechanisms responsible for the transport deficits and whether they preferentially affect α-motor neuron (MN) subtypes remain unresolved. Here, we report that stimulation of wild-type neurons with brain-derived neurotrophic factor (BDNF) enhances trafficking of signalling endosomes specifically in fast MNs (FMNs). In early symptomatic SOD1G93A mice, FMNs display selective impairment of axonal transport and develop an insensitivity to BDNF stimulation, with pathology upregulating classical non-pro-survival receptors in muscles and sciatic nerves. Altogether, these data indicate that cell- and non-cell autonomous BDNF signalling is impaired in vulnerable SOD1G93A MNs, thus identifying a new key deficit in ALS amenable for future therapeutic interventions.

scholarly journals When Are Depolarizing GABAergic Responses Excitatory?

2021 ◽  
Vol 14 ◽  
Author(s):  
Werner Kilb
Keyword(s):  
Neuronal Excitability ◽  
Neuronal Development ◽  
Developmental Stages ◽  
Experimental Studies ◽  
Reversal Potential ◽  
Input Resistance ◽  
Gaba A ◽  
Theoretical Considerations

The membrane responses upon activation of GABA(A) receptors critically depend on the intracellular Cl− concentration ([Cl−]i), which is maintained by a set of transmembrane transporters for Cl−. During neuronal development, but also under several pathophysiological conditions, the prevailing expression of the Cl− loader NKCC1 and the low expression of the Cl− extruder KCC2 causes elevated [Cl−]i, which result in depolarizing GABAergic membrane responses. However, depolarizing GABAergic responses are not necessarily excitatory, as GABA(A) receptors also reduces the input resistance of neurons and thereby shunt excitatory inputs. To summarize our knowledge on the effect of depolarizing GABA responses on neuronal excitability, this review discusses theoretical considerations and experimental studies illustrating the relation between GABA conductances, GABA reversal potential and neuronal excitability. In addition, evidences for the complex spatiotemporal interaction between depolarizing GABAergic and glutamatergic inputs are described. Moreover, mechanisms that influence [Cl−]i beyond the expression of Cl− transporters are presented. And finally, several in vitro and in vivo studies that directly investigated whether GABA mediates excitation or inhibition during early developmental stages are summarized. In summary, these theoretical considerations and experimental evidences suggest that GABA can act as inhibitory neurotransmitter even under conditions that maintain substantial depolarizing membrane responses.

scholarly journals Elevated Hoxb5b expands vagal neural crest pool and blocks enteric neuronal development in zebrafish

2021 ◽  
Author(s):  
Aubrey G. Adam Howard ◽  
Aaron C Nguyen ◽  
Joshua Tworig ◽  
Priya Ravisankar ◽  
Eileen Willey Singleton ◽  
...  
Keyword(s):  
Neural Crest ◽  
Neuronal Development ◽  
Developmental Stages ◽  
Stem Cell Population ◽  
Transgenic Zebrafish ◽  
Cellular Events ◽  
Comprehensive Knowledge ◽  
Numerous Cell ◽  
Timely Fashion ◽  
Adult Organism

Neural crest cells (NCCs) are a migratory, transient, and multipotent stem cell population essential to vertebrate embryonic development, contributing to numerous cell lineages in the adult organism. While great strides have been made in elucidating molecular and cellular events that drive NCC specification, comprehensive knowledge of the genetic factors that orchestrate NCC developmental programs is still far from complete. We discovered that elevated Hoxb5b levels promoted an expansion of zebrafish NCCs, which persisted throughout multiple stages of development. Correspondingly, elevated Hoxb5b also specifically expanded expression domains of the vagal NCC markers foxd3 and phox2bb. Increases in NCCs were most apparent after pulsed ectopic Hoxb5b expression at early developmental stages, rather than later during differentiation stages, as determined using a novel transgenic zebrafish line. The increase in vagal NCCs early in development led to supernumerary Phox2b+ enteric neural progenitors, while leaving many other NCC-derived tissues without an overt phenotype. Surprisingly, these NCC-derived enteric progenitors failed to expand properly into sufficient quantities of enterically fated neurons and stalled in the gut tissue. These results suggest that while Hoxb5b participates in vagal NCC development as a driver of progenitor expansion, the supernumerary, ectopically localized NCC fail to initiate expansion programs in timely fashion in the gut. All together, these data point to a model in which Hoxb5b regulates NCCs both in a tissue specific and temporally restricted manner.

scholarly journals Germ granules prevent accumulation of somatic transcripts in the adult C. elegans germline

2016 ◽  
Author(s):  
Andrew Kekūpa’a Knutson ◽  
Thea Egelhofer ◽  
Andreas Rechtsteiner ◽  
Susan Strome
Keyword(s):  
Germ Cell ◽  
Cell Fate ◽  
Single Molecule ◽  
Germ Cells ◽  
Neuronal Development ◽  
Developmental Stages ◽  
Developmental Potential ◽  
P Granules ◽  
Germ Granules ◽  
Rna Accumulation

ABSTRACTThe germ cells of multicellular organisms protect their developmental potential through specialized mechanisms. A shared feature of germ cells from worms to humans is the presence of non-membrane-bound ribonucleoprotein organelles called germ granules. Depletion of germ granules in Caenorhabditis elegans (i.e., P granules) leads to sterility and in some germlines expression of the neuronal transgene unc-119::gfp and the muscle myosin MYO-3. Thus, P granules are hypothesized to maintain germ cell totipotency by preventing somatic development, although the mechanism by which P granules carry out this function is unknown. In this study, we performed transcriptome and single molecule RNA-FISH analyses of dissected P-granule-depleted gonads at different developmental stages. Our results demonstrate that P granules are necessary for adult germ cells to down-regulate spermatogenesis RNAs and to prevent the accumulation of numerous soma-specific RNAs. P-granule-depleted gonads that express the unc-119::gfp transgene also express many other genes involved in neuronal development and concomitantly lose expression of germ cell fate markers. Finally, we show that removal of either of two critical P-granule components, PGL-1 or GLH-1, is sufficient to cause germ cells to express UNC-119::GFP and MYO-3 and to display RNA accumulation defects similar to those observed after depletion of P granules. Our data identify P granules as critical modulators of the germline transcriptome and guardians of germ cell fate.

scholarly journals Quantitative mapping of transcriptome and proteome dynamics during polarization of human iPSC-derived neurons

2020 ◽  
Author(s):  
Feline W. Lindhout ◽  
Robbelien Kooistra ◽  
Sybren Portegies ◽  
Lotte J. Herstel ◽  
Riccardo Stucchi ◽  
...  
Keyword(s):  
Neuronal Development ◽  
Developmental Stages ◽  
Expression Profiles ◽  
Model Systems ◽  
Human Model ◽  
Neuronal Stem Cells ◽  
Axon Development ◽  
Electrophysiological Responses ◽  
Human Neurons ◽  
Human Ipsc

ABSTRACTEarly neuronal development is a well-coordinated process in which neuronal stem cells differentiate into polarized neurons. This process has been well studied in classical non-human model systems, but to what extent this is recapitulated in human neurons remains unclear. To study neuronal polarization in human neurons, we cultured human iPSC-derived neurons, characterized early developmental stages, measured electrophysiological responses, and systematically profiled transcriptomic and proteomic dynamics during these steps. We found extensive remodeling of the neuron transcriptome and proteome, with altered mRNA expression of ~1,100 genes and different expression profiles of ~1,500 proteins during neuronal differentiation and polarization. We also identified a distinct stage in axon development marked by an increase in microtubule remodeling and apparent relocation of the axon initial segment from the distal to proximal axon. Our comprehensive characterization and quantitative map of transcriptome and proteome dynamics provides a solid framework for studying polarization in human neurons.

scholarly journals Magnesium Is a Key Player in Neuronal Maturation and Neuropathology

2019 ◽  
Vol 20 (14) ◽  
pp. 3439 ◽  
Author(s):  
Ryu Yamanaka ◽  
Yutaka Shindo ◽  
Kotaro Oka
Keyword(s):  
Mammalian Cells ◽  
Neuronal Development ◽  
Developmental Stages ◽  
Regulatory System ◽  
Cell Types ◽  
Research Field ◽  
Cell Phenotype ◽  
Enzymatic Reactions ◽  
Cellular Processes ◽  
Normal Functions

Magnesium (Mg) is the second most abundant cation in mammalian cells, and it is essential for numerous cellular processes including enzymatic reactions, ion channel functions, metabolic cycles, cellular signaling, and DNA/RNA stabilities. Because of the versatile and universal nature of Mg2+, the homeostasis of intracellular Mg2+ is physiologically linked to growth, proliferation, differentiation, energy metabolism, and death of cells. On the cellular and tissue levels, maintaining Mg2+ within optimal levels according to the biological context, such as cell types, developmental stages, extracellular environments, and pathophysiological conditions, is crucial for development, normal functions, and diseases. Hence, Mg2+ is pathologically involved in cancers, diabetes, and neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, and demyelination. In the research field regarding the roles and mechanisms of Mg2+ regulation, numerous controversies caused by its versatility and complexity still exist. As Mg2+, at least, plays critical roles in neuronal development, healthy normal functions, and diseases, appropriate Mg2+ supplementation exhibits neurotrophic effects in a majority of cases. Hence, the control of Mg2+ homeostasis can be a candidate for therapeutic targets in neuronal diseases. In this review, recent results regarding the roles of intracellular Mg2+ and its regulatory system in determining the cell phenotype, fate, and diseases in the nervous system are summarized, and an overview of the comprehensive roles of Mg2+ is provided.

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