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.

The role of receptor protein tyrosine phosphatase α in neuronal differentiation of embryonic stem cells

1996 ◽  
Vol 91 (2) ◽  
pp. 304-307 ◽  
Author(s):  
Wouter G. van Inzen ◽  
Maikel P. Peppelenbosch ◽  
Maria W.M. van den Brand ◽  
Leon G.J. Tertoolen ◽  
Siegfried de Laat
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Neuronal Differentiation ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Embryonic Stem ◽  
Receptor Protein ◽  
Protein Tyrosine ◽  
Receptor Protein Tyrosine Phosphatase

Embryo biotechnology in the dog: a review

2010 ◽  
Vol 22 (7) ◽  
pp. 1049 ◽  
Author(s):  
Sylvie Chastant-Maillard ◽  
Martine Chebrout ◽  
Sandra Thoumire ◽  
Marie Saint-Dizier ◽  
Marc Chodkiewicz ◽  
...  
Keyword(s):  
Mammalian Species ◽  
Embryonic Stem ◽  
Reproductive Technologies ◽  
Reproductive Physiology ◽  
Biological Models ◽  
The Past ◽  
Fertilisation Rate

Canine embryos are a scarce biological material because of difficulties in collecting in vivo-produced embryos and the inability, to date, to produce canine embryos in vitro. The procedure for the transfer of in vivo-produced embryos has not been developed adequately, with only six attempts reported in the literature that have resulted in the birth of 45 puppies. In vitro, the fertilisation rate is particularly low (∼10%) and the incidence of polyspermy particularly high. So far, no puppy has been obtained from an in vitro-produced embryo. In contrast, cloning of somatic cells has been used successfully over the past 4 years, with the birth of 41 puppies reported in the literature, a yield that is comparable to that for other mammalian species. Over the same period, canine embryonic stem sells and transgenic cloned dogs have been obtained. Thus, the latest reproductive technologies are further advanced than in vitro embryo production. The lack of fundamental studies on the specific features of reproductive physiology and developmental biology in the canine is regrettable in view of the increasing role of dogs in our society and of the current demand for new biological models in biomedical technology.

Analysis of the role of interleukin-1β (IL-1β)in vivo by gene targeting in embryonic stem (ES) cells

Cytokine ◽  
1994 ◽  
Vol 6 (5) ◽  
pp. 574
Author(s):  
L. Shornick ◽  
P. De Togni ◽  
S. Mariathasan ◽  
A. Fick ◽  
J. Goellner ◽  
...  
Keyword(s):  
Gene Targeting ◽  
Es Cells ◽  
Embryonic Stem ◽  
Interleukin 1Β

scholarly journals MOZ and BMI1 play opposing roles during Hox gene activation in ES cells and in body segment identity specification in vivo

2015 ◽  
Vol 112 (17) ◽  
pp. 5437-5442 ◽  
Author(s):  
Bilal N. Sheikh ◽  
Natalie L. Downer ◽  
Belinda Phipson ◽  
Hannah K. Vanyai ◽  
Andrew J. Kueh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Es Cells ◽  
Gene Activation ◽  
Embryonic Stem ◽  
Mrna Levels ◽  
Body Segment ◽  
Initial Activation ◽  
Activation Phase

Hox genes underlie the specification of body segment identity in the anterior–posterior axis. They are activated during gastrulation and undergo a dynamic shift from a transcriptionally repressed to an active chromatin state in a sequence that reflects their chromosomal location. Nevertheless, the precise role of chromatin modifying complexes during the initial activation phase remains unclear. In the current study, we examined the role of chromatin regulators during Hox gene activation. Using embryonic stem cell lines lacking the transcriptional activator MOZ and the polycomb-family repressor BMI1, we showed that MOZ and BMI1, respectively, promoted and repressed Hox genes during the shift from the transcriptionally repressed to the active state. Strikingly however, MOZ but not BMI1 was required to regulate Hox mRNA levels after the initial activation phase. To determine the interaction of MOZ and BMI1 in vivo, we interrogated their role in regulating Hox genes and body segment identity using Moz;Bmi1 double deficient mice. We found that the homeotic transformations and shifts in Hox gene expression boundaries observed in single Moz and Bmi1 mutant mice were rescued to a wild type identity in Moz;Bmi1 double knockout animals. Together, our findings establish that MOZ and BMI1 play opposing roles during the onset of Hox gene expression in the ES cell model and during body segment identity specification in vivo. We propose that chromatin-modifying complexes have a previously unappreciated role during the initiation phase of Hox gene expression, which is critical for the correct specification of body segment identity.

scholarly journals SFRP1 and SFRP2 Dose-Dependently Regulate Midbrain Dopamine Neuron Development In Vivo and in Embryonic Stem Cells

Stem Cells ◽  
2012 ◽  
Vol 30 (5) ◽  
pp. 865-875 ◽  
Author(s):  
Julianna Kele ◽  
Emma R. Andersson ◽  
J. Carlos Villaescusa ◽  
Lukas Cajanek ◽  
Clare L. Parish ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Dopamine Neuron ◽  
Neuron Development ◽  
Midbrain Dopamine

scholarly journals Dopamine modulates the size of striatal projection neuron ensembles

2019 ◽  
Author(s):  
Marta Maltese ◽  
Jeffrey R. March ◽  
Alexander G. Bashaw ◽  
Nicolas X. Tritsch
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Projection Neuron ◽  
Projection Neurons ◽  
Voluntary Movements ◽  
Indirect Pathway ◽  
Two Photon ◽  
Direct Pathway ◽  
Brain Circuits

SUMMARYDopamine (DA) is a critical modulator of brain circuits that control voluntary movements, but our understanding of its influence on the activity of target neurons in vivo remains limited. Here, we use two-photon Ca2+ imaging to simultaneously monitor the activity of direct and indirect-pathway spiny projection neurons (SPNs) in the striatum of behaving mice during acute and prolonged manipulations of DA signaling. We find that, contrary to prevailing models, DA does not modulate activity rates in either pathway strongly or differentially. Instead, DA exerts a prominent influence on the overall number of direct and indirect pathway SPNs recruited during behavior. Chronic loss of midbrain DA neurons in a model of Parkinson’s disease selectively impacts direct pathway ensembles and profoundly alters how they respond to DA elevation. Our results indicate that DA regulates striatal output by dynamically reconfiguring its sparse ensemble code and provide novel insights into the pathophysiology of Parkinson’s disease.

scholarly journals Dichotomous role of Shp2 for naïve and primed pluripotency maintenance in embryonic stem cells

2021 ◽  
Author(s):  
Seong Min Kim ◽  
Eun-Ji Kwon ◽  
Yun-Jeong Kim ◽  
Young-Hyun Go ◽  
Ji-Young Oh ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Erk Signaling ◽  
Differentiation Potential ◽  
Stat3 Signaling ◽  
Stat3 Phosphorylation ◽  
Pluripotency Maintenance

Abstract The requirement of the Mek1 inhibitor (iMek1) during naïve pluripotency maintenance results from the activation of the Mek1-Erk1/2 (Mek/Erk) signaling pathway upon leukemia inhibitory factor (LIF) stimulation. Through a meta-analysis of previous genome-wide screening for negative regulators of naïve pluripotency, Ptpn11 (encoding the Shp2 protein, which serves both as a tyrosine phosphatase and putative adapter), was predicted as one of the key factors for the negative modulation of naïve pluripotency through LIF-dependent Jak/Stat3 signaling. Using an isogenic pair of naïve and primed mouse embryonic stem cells (mESCs), we demonstrated the differential role of Shp2 in naïve and primed pluripotency. Loss of Shp2 increased naive pluripotency by promoting Jak/Stat3 signaling and disturbed in vivo differentiation potential. In sharp contrast, Shp2 depletion significantly impeded the self-renewal of ESCs under primed culture conditions, which was concurrent with a reduction in Mek/Erk signaling. Similarly, upon treatment with an allosteric Shp2 inhibitor (iShp2), the cells sustained Stat3 phosphorylation and decoupled Mek/Erk signaling, thus replacing the use of iMek1 not only for maintenance but also for the establishment of naïve ESCs through reprogramming. Taken together, our findings highlight the differential roles of Shp2 in naïve and primed pluripotency and propose the usage of iShp2 instead of iMek1 for the efficient maintenance and establishment of naïve pluripotency.

scholarly journals Fezf2 transient expression via modRNA with concurrent SIRT1 inhibition enhances differentiation of cortical subcerebral / corticospinal neuron identity from mES cells

2020 ◽  
Author(s):  
Cameron Sadegh ◽  
Wataru Ebina ◽  
Anthony C. Arvanites ◽  
Lance S. Davidow ◽  
Lee L. Rubin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cortical Neurons ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Sirtuin 1 ◽  
Projection Neurons ◽  
Specific Expression ◽  
Specific Differentiation

AbstractDuring late embryonic development of the cerebral cortex, the major class of cortical output neurons termed subcerebral projection neurons (SCPN; including the predominant population of corticospinal neurons, CSN) and the class of interhemispheric callosal projection neurons (CPN) initially express overlapping molecular controls that later undergo subtype-specific refinements. Such molecular refinements are largely absent in heterogeneous, maturation-stalled, neocortical-like neurons (termed “cortical” here) spontaneously generated by established embryonic stem cell (ES) and induced pluripotent stem cell (iPSC) differentiation. Building on recently identified central molecular controls over SCPN development, we used a combination of synthetic modified mRNA (modRNA) for Fezf2, the central transcription factor controlling SCPN specification, and small molecule screening to investigate whether distinct chromatin modifiers might complement Fezf2 functions to promote SCPN-specific differentiation by mouse ES (mES)-derived cortical-like neurons. We find that the inhibition of a specific histone deacetylase, Sirtuin 1 (SIRT1), enhances refinement of SCPN subtype molecular identity by both mES-derived cortical-like neurons and primary dissociated E12.5 mouse cortical neurons. In vivo, we identify that SIRT1 is specifically expressed by CPN, but not SCPN, during late embryonic and postnatal differentiation. Together, these data indicate that SIRT1 has neuronal subtype-specific expression in the mouse cortex in vivo, and its inhibition enhances subtype-specific differentiation of highly clinically relevant SCPN / CSN cortical neurons in vitro.

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.

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