scholarly journals New Insights Into the Intricacies of Proneural Gene Regulation in the Embryonic and Adult Cerebral Cortex

2021 ◽  
Vol 14 ◽  
Author(s):  
Ana-Maria Oproescu ◽  
Sisu Han ◽  
Carol Schuurmans
Keyword(s):  
Stem Cells ◽  
Cerebral Cortex ◽  
Protein Interactions ◽  
Neural Progenitor Cells ◽  
Target Genes ◽  
Brain Regions ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Proneural Gene ◽  
Molecular Control

Historically, the mammalian brain was thought to lack stem cells as no new neurons were found to be made in adulthood. That dogma changed ∼25 years ago with the identification of neural stem cells (NSCs) in the adult rodent forebrain. However, unlike rapidly self-renewing mature tissues (e.g., blood, intestinal crypts, skin), the majority of adult NSCs are quiescent, and those that become ‘activated’ are restricted to a few neurogenic zones that repopulate specific brain regions. Conversely, embryonic NSCs are actively proliferating and neurogenic. Investigations into the molecular control of the quiescence-to-proliferation-to-differentiation continuum in the embryonic and adult brain have identified proneural genes encoding basic-helix-loop-helix (bHLH) transcription factors (TFs) as critical regulators. These bHLH TFs initiate genetic programs that remove NSCs from quiescence and drive daughter neural progenitor cells (NPCs) to differentiate into specific neural cell subtypes, thereby contributing to the enormous cellular diversity of the adult brain. However, new insights have revealed that proneural gene activities are context-dependent and tightly regulated. Here we review how proneural bHLH TFs are regulated, with a focus on the murine cerebral cortex, drawing parallels where appropriate to other organisms and neural tissues. We discuss upstream regulatory events, post-translational modifications (phosphorylation, ubiquitinylation), protein–protein interactions, epigenetic and metabolic mechanisms that govern bHLH TF expression, stability, localization, and consequent transactivation of downstream target genes. These tight regulatory controls help to explain paradoxical findings of changes to bHLH activity in different cellular contexts.

scholarly journals An architectonic type principle in the development of laminar patterns of cortico-cortical connections

2021 ◽  
Author(s):  
Sarah F. Beul ◽  
Alexandros Goulas ◽  
Claus C. Hilgetag
Keyword(s):  
Structural Connectivity ◽  
Macaque Monkey ◽  
Brain Regions ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Cortical Connections ◽  
Cortical Projections ◽  
Structural Connections ◽  
High Degree ◽  
The Brain

AbstractStructural connections between cortical areas form an intricate network with a high degree of specificity. Many aspects of this complex network organization in the adult mammalian cortex are captured by an architectonic type principle, which relates structural connections to the architectonic differentiation of brain regions. In particular, the laminar patterns of projection origins are a prominent feature of structural connections that varies in a graded manner with the relative architectonic differentiation of connected areas in the adult brain. Here we show that the architectonic type principle is already apparent for the laminar origins of cortico-cortical projections in the immature cortex of the macaque monkey. We find that prenatal and neonatal laminar patterns correlate with cortical architectonic differentiation, and that the relation of laminar patterns to architectonic differences between connected areas is not substantially altered by the complete loss of visual input. Moreover, we find that the degree of change in laminar patterns that projections undergo during development varies in proportion to the relative architectonic differentiation of the connected areas. Hence, it appears that initial biases in laminar projection patterns become progressively strengthened by later developmental processes. These findings suggest that early neurogenetic processes during the formation of the brain are sufficient to establish the characteristic laminar projection patterns. This conclusion is in line with previously suggested mechanistic explanations underlying the emergence of the architectonic type principle and provides further constraints for exploring the fundamental factors that shape structural connectivity in the mammalian brain.

scholarly journals The Expression and Distributions of ANP32A in the Developing Brain

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Shanshan Wang ◽  
Yunliang Wang ◽  
Qingshan Lu ◽  
Xinshan Liu ◽  
Fuyu Wang ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Fetal Brain ◽  
Tissue Expression ◽  
Developing Brain ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Dependent Manner ◽  
Growing Up ◽  
Embryonic Mouse ◽  
And Function

Acidic (leucine-rich) nuclear phosphoprotein 32 family, member A (ANP32A), has multiple functions involved in neuritogenesis, transcriptional regulation, and apoptosis. However, whether ANP32A has an effect on the mammalian developing brain is still in question. In this study, it was shown that brain was the organ that expressed the most abundant ANP32A by human multiple tissue expression (MTE) array. The distribution of ANP32A in the different adult brain areas was diverse dramatically, with high expression in cerebellum, temporal lobe, and cerebral cortex and with low expression in pons, medulla oblongata, and spinal cord. The expression of ANP32A was higher in the adult brain than in the fetal brain of not only humans but also mice in a time-dependent manner. ANP32A signals were dispersed accordantly in embryonic mouse brain. However, ANP32A was abundant in the granular layer of the cerebellum and the cerebral cortex when the mice were growing up, as well as in the Purkinje cells of the cerebellum. The variation of expression levels and distribution of ANP32A in the developing brain would imply that ANP32A may play an important role in mammalian brain development, especially in the differentiation and function of neurons in the cerebellum and the cerebral cortex.

scholarly journals Insights into the Biology and Therapeutic Applications of Neural Stem Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-18 ◽  
Author(s):  
Lachlan Harris ◽  
Oressia Zalucki ◽  
Michael Piper ◽  
Julian Ik-Tsen Heng
Keyword(s):  
Stem Cells ◽  
Cerebral Cortex ◽  
Brain Injury ◽  
Neural Stem Cells ◽  
Human Brain ◽  
Therapeutic Potential ◽  
Biological Significance ◽  
Adult Brain ◽  
Cognitive Capacity ◽  
Molecular Characteristics

The cerebral cortex is essential for our higher cognitive functions and emotional reasoning. Arguably, this brain structure is the distinguishing feature of our species, and yet our remarkable cognitive capacity has seemingly come at a cost to the regenerative capacity of the human brain. Indeed, the capacity for regeneration and neurogenesis of the brains of vertebrates has declined over the course of evolution, from fish to rodents to primates. Nevertheless, recent evidence supporting the existence of neural stem cells (NSCs) in the adult human brain raises new questions about the biological significance of adult neurogenesis in relation to ageing and the possibility that such endogenous sources of NSCs might provide therapeutic options for the treatment of brain injury and disease. Here, we highlight recent insights and perspectives on NSCs within both the developing and adult cerebral cortex. Our review of NSCs during development focuses upon the diversity and therapeutic potential of these cells for use in cellular transplantation and in the modeling of neurodevelopmental disorders. Finally, we describe the cellular and molecular characteristics of NSCs within the adult brain and strategies to harness the therapeutic potential of these cell populations in the treatment of brain injury and disease.

scholarly journals Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain

2015 ◽  
Vol 112 (22) ◽  
pp. 6855-6862 ◽  
Author(s):  
Loyal A. Goff ◽  
Abigail F. Groff ◽  
Martin Sauvageau ◽  
Zachary Trayes-Gibson ◽  
Diana B. Sanchez-Gomez ◽  
...  
Keyword(s):  
Neural Development ◽  
Expression Patterns ◽  
Noncoding Rnas ◽  
Brain Regions ◽  
Long Noncoding Rnas ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Endogenous Expression ◽  
Spatiotemporal Expression

Long noncoding RNAs (lncRNAs) have been implicated in numerous cellular processes including brain development. However, the in vivo expression dynamics and molecular pathways regulated by these loci are not well understood. Here, we leveraged a cohort of 13 lncRNA-null mutant mouse models to investigate the spatiotemporal expression of lncRNAs in the developing and adult brain and the transcriptome alterations resulting from the loss of these lncRNA loci. We show that several lncRNAs are differentially expressed both in time and space, with some presenting highly restricted expression in only selected brain regions. We further demonstrate altered regulation of genes for a large variety of cellular pathways and processes upon deletion of the lncRNA loci. Finally, we found that 4 of the 13 lncRNAs significantly affect the expression of several neighboring protein-coding genes in a cis-like manner. By providing insight into the endogenous expression patterns and the transcriptional perturbations caused by deletion of the lncRNA locus in the developing and postnatal mammalian brain, these data provide a resource to facilitate future examination of the specific functional relevance of these genes in neural development, brain function, and disease.

scholarly journals The Strange Case of Jekyll and Hyde: Parallels Between Neural Stem Cells and Glioblastoma-Initiating Cells

2021 ◽  
Vol 10 ◽  
Author(s):  
David Bakhshinyan ◽  
Neil Savage ◽  
Sabra Khalid Salim ◽  
Chitra Venugopal ◽  
Sheila K. Singh
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Current Therapies ◽  
Multipotent Differentiation ◽  
Radial Glial ◽  
Divergent Behavior ◽  
Genetic Profiles

During embryonic development, radial glial precursor cells give rise to neural lineages, and a small proportion persist in the adult mammalian brain to contribute to long-term neuroplasticity. Neural stem cells (NSCs) reside in two neurogenic niches of the adult brain, the hippocampus and the subventricular zone (SVZ). NSCs in the SVZ are endowed with the defining stem cell properties of self-renewal and multipotent differentiation, which are maintained by intrinsic cellular programs, and extrinsic cellular and niche-specific interactions. In glioblastoma, the most aggressive primary malignant brain cancer, a subpopulation of cells termed glioblastoma stem cells (GSCs) exhibit similar stem-like properties. While there is an extensive overlap between NSCs and GSCs in function, distinct genetic profiles, transcriptional programs, and external environmental cues influence their divergent behavior. This review highlights the similarities and differences between GSCs and SVZ NSCs in terms of their gene expression, regulatory molecular pathways, niche organization, metabolic programs, and current therapies designed to exploit these differences.

scholarly journals An immune-CNS axis activates remote hippocampal stem cells following Spinal Transection Injury

2018 ◽  
Author(s):  
Sascha Dehler ◽  
Pak-Kin Lou ◽  
Maxim Skabkin ◽  
Sabrina Laudenklos ◽  
Andreas Neumann ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Activity ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Spinal Transection ◽  
Thoracic Spinal ◽  
Close Proximity ◽  
Stem Cell Activity ◽  
External Stimuli ◽  
Adult Mammalian Brain

AbstractExternal stimuli such as injury, learning, or stress influence the production of neurons by neural stem cells (NSCs) in the adult mammalian brain. These external stimuli directly impact stem cell activity by influencing areas directly connected or in close proximity to the neurogenic niches of the adult brain. However, very little is known on how distant injuries affect NSC activation state. In this study we demonstrate that a thoracic spinal transection injury activates the distally located hippocampal-NSCs. This activation leads to a transient increase production of neurons that functionally integrate to improve animal’s performance in hippocampal-related memory tasks. We further show that interferon-CD95 signaling is required to promote injury-mediated activation of remote NSCs. Thus, we identify an immune-CNS axis responsible for injury-mediated activation of remotely located NSCs.

scholarly journals D-cysteine is an endogenous regulator of neural progenitor cell dynamics in the mammalian brain

2021 ◽  
Vol 118 (39) ◽  
pp. e2110610118
Author(s):  
Evan R. Semenza ◽  
Maged M. Harraz ◽  
Efrat Abramson ◽  
Adarsha P. Malla ◽  
Chirag Vasavda ◽  
...  
Keyword(s):  
High Performance ◽  
Neural Progenitor Cells ◽  
Neural Progenitor Cell ◽  
Neural Progenitor ◽  
Adult Brain ◽  
Luciferase Assay ◽  
Mammalian Brain ◽  
Embryonic Mouse ◽  
Kinase Substrate

d-amino acids are increasingly recognized as important signaling molecules in the mammalian central nervous system. However, the d-stereoisomer of the amino acid with the fastest spontaneous racemization ratein vitro in vitro, cysteine, has not been examined in mammals. Using chiral high-performance liquid chromatography and a stereospecific luciferase assay, we identify endogenous d-cysteine in the mammalian brain. We identify serine racemase (SR), which generates the N-methyl-d-aspartate (NMDA) glutamate receptor coagonist d-serine, as a candidate biosynthetic enzyme for d-cysteine. d-cysteine is enriched more than 20-fold in the embryonic mouse brain compared with the adult brain. d-cysteine reduces the proliferation of cultured mouse embryonic neural progenitor cells (NPCs) by ∼50%, effects not shared with d-serine or l-cysteine. The antiproliferative effect of d-cysteine is mediated by the transcription factors FoxO1 and FoxO3a. The selective influence of d-cysteine on NPC proliferation is reflected in overgrowth and aberrant lamination of the cerebral cortex in neonatal SR knockout mice. Finally, we perform an unbiased screen for d-cysteine–binding proteins in NPCs by immunoprecipitation with a d-cysteine–specific antibody followed by mass spectrometry. This approach identifies myristoylated alanine-rich C-kinase substrate (MARCKS) as a putative d-cysteine–binding protein. Together, these results establish endogenous mammalian d-cysteine and implicate it as a physiologic regulator of NPC homeostasis in the developing brain.

scholarly journals Anatomical development of the cerebellothalamic tract in embryonic mice

2019 ◽  
Author(s):  
Daniël B. Dumas ◽  
Simona V. Gornati ◽  
Youri Adolfs ◽  
Tomomi Shimogori ◽  
R. Jeroen Pasterkamp ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
Light Sheet ◽  
Autism Spectrum ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Wide Field ◽  
Thalamic Nuclei ◽  
Cortical Regions

AbstractCerebellar projections to the thalamus are a pivotal connection in cerebello-cerebral interactions. Apart from its role in coordinating sensorimotor integration in the adult brain, the cerebello-thalamic projection has also been implemented in developmental disorders, such as autism spectrum disorders. Although the development of the cerebellum, thalamus and cerebral cortex have been studied in many species, a detailed description of the ontogeny of the mammalian cerebello-thalamic tract (CbT) is currently missing. Here we investigated the development of the CbT at embryonic stages using transgenic Ntsr1-Cre/Ai14 mice and in utero electroporation (IUE) of wild type mice. Wide-field, confocal and 3D light-sheet imaging of immunohistochemical stainings showed that CbT fibers arrive in the prethalamus between E14.5 and E15.5, but only invade the thalamus after E16.5. We quantified the spread of CbT fibers throughout the various thalamic nuclei and found that at E17.5 and E18.5 the ventrolateral, ventromedial and parafascicular nuclei, but also the mediodorsal and posterior complex become increasingly innervated. Several CbT fiber varicosities colocalize with vGluT2, indicating that already from E18.5 the CbT synapse in various thalamic nuclei. Our results contribute to the construction of a frame of reference on the anatomical development of the CbT, which will help to guide future experiments investigating neurodevelopmental disorders.Significance statementUsing various microscopic approaches, we investigated the anatomical development of the fiber tract between the cerebellum and thalamus, one of the major mammalian brain connections. Our results show that in mice cerebellar axons wait outside of the thalamus from embryonic day (E)15.5 until E17.5 before invading the thalamic complex. Cerebellar axons establish vGluT2-positive synapses at E18.5 throughout various thalamic nuclei, each of which subsequently develops its connections with dedicated cerebral cortical regions. Our data thereby advocate the cerebellar influence on the maturation of the thalamus and connected cerebral cortex. This knowledge can help to guide future experiments into neurodevelopmental disorders affecting cerebello-thalamo-cortical networks.

Neuroregenerative Medicine in TBI

Neurotrauma ◽  
2018 ◽  
pp. 359-372
Author(s):  
Jinhui Chen ◽  
Xiaoting Wang ◽  
Xiang Gao
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Cell Death ◽  
Large Population ◽  
Brain Regions ◽  
Adult Brain ◽  
Great Promise ◽  
Pathological Changes ◽  
Neural Repair ◽  
Neuroregenerative Medicine

Traumatic brain injury (TBI) is affecting a large population with permanent physical disabilities and neurobehavioral abnormalities worldwide. Cell death in multiple brain regions is one of the most common pathological changes seen after TBI. Neuronal replacement then represents an urgent need for functional recovery. Neural stem cells (NSC) to mediate endogenous neurogenesis in the adult brain holds great promise for neural repair by replacing dead neurons and rebuilding damaged connections. It has been shown that TBI promotes NSC proliferation, detected in both the forebrain and the hippocampus, displaying an intrinsic neuroplasticity in response to injury. Thus, endogenous neurogenesis is an appropriate target for clinical interference aimed at neural repair post-trauma.

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