scholarly journals Cited2 Regulates Neocortical Layer II/III Generation and Somatosensory Callosal Projection Neuron Development and Connectivity

2016 ◽  
Vol 36 (24) ◽  
pp. 6403-6419 ◽  
Author(s):  
Ryann M. Fame ◽  
Jessica L. MacDonald ◽  
Sally L. Dunwoodie ◽  
Emi Takahashi ◽  
Jeffrey D. Macklis
Keyword(s):  
Projection Neuron ◽  
Neuron Development ◽  
Callosal Projection

scholarly journals Re-establishment of the epigenetic state and rescue of kinome deregulation in Ts65Dn mice upon treatment with green tea extract and environmental enrichment

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
I. De Toma ◽  
M. Ortega ◽  
S. Catuara-Solarz ◽  
C. Sierra ◽  
E. Sabidó ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Green Tea ◽  
Environmental Enrichment ◽  
Projection Neuron ◽  
Synaptic Proteins ◽  
Chromosome 21 ◽  
Neuron Development ◽  
Epigenetic State ◽  
Neuronal Projection ◽  
Tea Extract

Abstract Down syndrome (DS) is the main genetic cause of intellectual disability due to triplication of human chromosome 21 (HSA21). Although there is no treatment for intellectual disability, environmental enrichment (EE) and the administration of green tea extracts containing epigallocatechin-3-gallate (EGCG) improve cognition in mouse models and individuals with DS. Using proteome, and phosphoproteome analysis in the hippocampi of a DS mouse model (Ts65Dn), we investigated the possible mechanisms underlying the effects of green tea extracts, EE and their combination. Our results revealed disturbances in cognitive-related (synaptic proteins, neuronal projection, neuron development, microtubule), GTPase/kinase activity and chromatin proteins. Green tea extracts, EE, and their combination restored more than 70% of the phosphoprotein deregulation in Ts65Dn, and induced possible compensatory effects. Our downstream analyses indicate that re-establishment of a proper epigenetic state and rescue of the kinome deregulation may contribute to the cognitive rescue induced by green tea extracts.

scholarly journals An evolutionarily acquired microRNA shapes development of mammalian cortical projections

2020 ◽  
Author(s):  
Jessica L Diaz ◽  
Verl B Siththanandan ◽  
Victoria Lu ◽  
Nicole Gonzalez-Nava ◽  
Lincoln Pasquina ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Cognitive Skills ◽  
Corticospinal Tract ◽  
Projection Neuron ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Complex Motor ◽  
Callosal Projection ◽  
Cortical Projection Neuron

AbstractThe corticospinal tract is unique to mammals and the corpus callosum is unique to placental mammals (eutherians). The emergence of these structures is thought to underpin the evolutionary acquisition of complex motor and cognitive skills. Corticospinal motor neurons (CSMN) and callosal projection neurons (CPN) are the archetypal projection neurons of the corticospinal tract and corpus callosum, respectively. Although a number of conserved transcriptional regulators of CSMN and CPN development have been identified in vertebrates, none are unique to mammals and most are co-expressed across multiple projection neuron subtypes. Here, we discover seventeen CSMN-enriched microRNAs (miRNAs), fifteen of which map to a single genomic cluster that is exclusive to eutherians. One of these, miR-409-3p, promotes CSMN subtype identity in part via repression of LMO4, a key transcriptional regulator of CPN development. In vivo, miR-409-3p is sufficient to convert deep-layer CPN into CSMN. This is the first demonstration of an evolutionarily acquired miRNA in eutherians that refines cortical projection neuron subtype development. Our findings implicate miRNAs in the eutherians’ increase in neuronal subtype and projection diversity, the anatomic underpinnings of their complex behavior.Significance StatementThe mammalian central nervous system contains unique projections from the cerebral cortex thought to underpin complex motor and cognitive skills, including the corticospinal tract and corpus callosum. The neurons giving rise to these projections - corticospinal and callosal projection neurons - develop from the same progenitors, but acquire strikingly different fates. The broad evolutionary conservation of known genes controlling cortical projection neuron fates raises the question of how the more narrowly conserved corticospinal and callosal projections evolved. We identify a microRNA cluster selectively expressed by corticospinal projection neurons and exclusive to placental mammals. One of these microRNAs promotes corticospinal fate via regulation of the callosal gene LMO4, suggesting a mechanism whereby microRNA regulation during development promotes evolution of neuronal diversity.

scholarly journals Zbtb20 Defines a Hippocampal Neuronal Identity Through Direct Repression of Genes That Control Projection Neuron Development in the Isocortex

2013 ◽  
Vol 24 (5) ◽  
pp. 1216-1229 ◽  
Author(s):  
Jakob V. Nielsen ◽  
Mads Thomassen ◽  
Kjeld Møllgård ◽  
Jens Noraberg ◽  
Niels A. Jensen
Keyword(s):  
Projection Neuron ◽  
Neuron Development ◽  
Neuronal Identity

scholarly journals Satb2 Regulates Callosal Projection Neuron Identity in the Developing Cerebral Cortex

Neuron ◽  
2008 ◽  
Vol 57 (3) ◽  
pp. 364-377 ◽  
Author(s):  
Elizabeth A. Alcamo ◽  
Laura Chirivella ◽  
Marcel Dautzenberg ◽  
Gergana Dobreva ◽  
Isabel Fariñas ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Projection Neuron ◽  
Callosal Projection

scholarly journals Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons

2015 ◽  
Vol 112 (44) ◽  
pp. 13693-13698 ◽  
Author(s):  
Adán de Salas-Quiroga ◽  
Javier Díaz-Alonso ◽  
Daniel García-Rincón ◽  
Floortje Remmers ◽  
David Vega ◽  
...  
Keyword(s):  
Prenatal Exposure ◽  
Cortical Neurons ◽  
Time Window ◽  
Projection Neuron ◽  
Fine Motor ◽  
Adult Offspring ◽  
Neuron Development ◽  
Cortical Projection ◽  
Genetic Ablation ◽  
The Impact

The CB1 cannabinoid receptor, the main target of Δ9-tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB1 receptor genetic ablation, and CB1-null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB1 expression-rescue strategy in a CB1-null background. Early and selective CB1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB1-null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB1-dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB1 signaling.

scholarly journals Mutual regulation between Satb2 and Fezf2 promotes subcerebral projection neuron identity in the developing cerebral cortex

2015 ◽  
Vol 112 (37) ◽  
pp. 11702-11707 ◽  
Author(s):  
William L. McKenna ◽  
Christian F. Ortiz-Londono ◽  
Thomas K. Mathew ◽  
Kendy Hoang ◽  
Sol Katzman ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Projection Neuron ◽  
Dependent Manner ◽  
Neuron Development ◽  
Cortical Projection ◽  
Expression Of Genes ◽  
Axon Development ◽  
Mutual Regulation ◽  
A Cell ◽  
Cortical Projection Neuron

Generation of distinct cortical projection neuron subtypes during development relies in part on repression of alternative neuron identities. It was reported that the special AT-rich sequence-binding protein 2 (Satb2) is required for proper development of callosal neuron identity and represses expression of genes that are essential for subcerebral axon development. Surprisingly, Satb2 has recently been shown to be necessary for subcerebral axon development. Here, we unravel a previously unidentified mechanism underlying this paradox. We show that SATB2 directly activates transcription of forebrain embryonic zinc finger 2 (Fezf2) and SRY-box 5 (Sox5), genes essential for subcerebral neuron development. We find that the mutual regulation between Satb2 and Fezf2 enables Satb2 to promote subcerebral neuron identity in layer 5 neurons, and to repress subcerebral characters in callosal neurons. Thus, Satb2 promotes the development of callosal and subcerebral neurons in a cell context-dependent manner.

scholarly journals Human-specific enrichment of schizophrenia risk-genes in callosal neurons of the developing neocortex

2021 ◽  
Author(s):  
Emanuela Zuccaro ◽  
Vanessa Murek ◽  
Kwanho Kim ◽  
Hsu-Hsin Chen ◽  
Sara Mancinelli ◽  
...  
Keyword(s):  
Disease Risk ◽  
Cell Types ◽  
Projection Neuron ◽  
Inhibitory Interneuron ◽  
Projection Neurons ◽  
Risk Genes ◽  
Neuropsychiatric Diseases ◽  
Excitatory Projection ◽  
Callosal Projection ◽  
Human Specific

SummaryHuman genetic studies have provided a wealth of information on genetic risk factors associated with neuropsychiatric diseases. However, whether different brain cell types are differentially affected in disease states and when in their development and maturation alterations occur is still poorly understood. Here we generated a longitudinal transcriptional map of excitatory projection neuron (PN) and inhibitory interneuron (IN) subtypes of the cerebral cortex, across a timeline of mouse embryonic and postnatal development, as well as fetal human cortex and human cortical organoids. We found that three types of gene signatures uniquely defined each cortical neuronal subtype: dynamic (developmental), adult (terminal), and constitutive (stable), with individual neuronal subtypes varying in the degree of similarity of their signatures between species. In particular, human callosal projection neurons (CPN) displayed the greatest species divergence, with molecular signatures highly enriched for non-coding, human-specific RNAs. Evaluating the association of neuronal class-specific signatures with neuropsychiatric disease risk genes using linkage disequilibrium score regression showed that schizophrenia risk genes were enriched in CPN identity signatures from human but not mouse cortex. Human cortical organoids confirmed the association with excitatory projection neurons. The data indicate that risk gene enrichment is both species- and cell type-specific. Our study reveals molecular determinants of cortical neuron diversification and identifies human callosal projection neurons as the most species-divergent population and a potentially vulnerable neuronal class in schizophrenia.

scholarly journals Endocannabinoid signalling in stem cells and cerebral organoids drives differentiation to deep layer projection neurons via CB1 receptors

Development ◽  
2020 ◽  
Vol 147 (24) ◽  
pp. dev192161
Author(s):  
Juan Paraíso-Luna ◽  
José Aguareles ◽  
Ricardo Martín ◽  
Ane C. Ayo-Martín ◽  
Samuel Simón-Sánchez ◽  
...  
Keyword(s):  
Neuronal Differentiation ◽  
Deep Layer ◽  
Embryonic Stem ◽  
Projection Neuron ◽  
Projection Neurons ◽  
Neuron Development ◽  
Receptor Agonists ◽  
Pluripotent Embryonic Stem Cell

ABSTRACTThe endocannabinoid (eCB) system, via the cannabinoid CB1 receptor, regulates neurodevelopment by controlling neural progenitor proliferation and neurogenesis. CB1 receptor signalling in vivo drives corticofugal deep layer projection neuron development through the regulation of BCL11B and SATB2 transcription factors. Here, we investigated the role of eCB signalling in mouse pluripotent embryonic stem cell-derived neuronal differentiation. Characterization of the eCB system revealed increased expression of eCB-metabolizing enzymes, eCB ligands and CB1 receptors during neuronal differentiation. CB1 receptor knockdown inhibited neuronal differentiation of deep layer neurons and increased upper layer neuron generation, and this phenotype was rescued by CB1 re-expression. Pharmacological regulation with CB1 receptor agonists or elevation of eCB tone with a monoacylglycerol lipase inhibitor promoted neuronal differentiation of deep layer neurons at the expense of upper layer neurons. Patch-clamp analyses revealed that enhancing cannabinoid signalling facilitated neuronal differentiation and functionality. Noteworthy, incubation with CB1 receptor agonists during human iPSC-derived cerebral organoid formation also promoted the expansion of BCL11B+ neurons. These findings unveil a cell-autonomous role of eCB signalling that, via the CB1 receptor, promotes mouse and human deep layer cortical neuron development.

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