Elevated FOXG1 and SOX2 in glioblastoma enforces neural stem cell identity through transcriptional control of cell cycle and epigenetic regulators

Glioblastoma multiforme (GBM) is an aggressive brain tumor driven by cells with hallmarks of neural stem (NS) cells. GBM stem cells frequently express high levels of the transcription factors FOXG1 and SOX2. Here we show that increased expression of these factors restricts astrocyte differentiation and can trigger dedifferentiation to a proliferative NS cell state. Transcriptional targets include cell cycle and epigenetic regulators (e.g., Foxo3, Plk1, Mycn, Dnmt1, Dnmt3b, and Tet3). Foxo3 is a critical repressed downstream effector that is controlled via a conserved FOXG1/SOX2-bound cis-regulatory element. Foxo3 loss, combined with exposure to the DNA methylation inhibitor 5-azacytidine, enforces astrocyte dedifferentiation. DNA methylation profiling in differentiating astrocytes identifies changes at multiple polycomb targets, including the promoter of Foxo3 In patient-derived GBM stem cells, CRISPR/Cas9 deletion of FOXG1 does not impact proliferation in vitro; however, upon transplantation in vivo, FOXG1-null cells display increased astrocyte differentiation and up-regulate FOXO3. In contrast, SOX2 ablation attenuates proliferation, and mutant cells cannot be expanded in vitro. Thus, FOXG1 and SOX2 operate in complementary but distinct roles to fuel unconstrained self-renewal in GBM stem cells via transcriptional control of core cell cycle and epigenetic regulators.H.B. was supported by a Wellcome Trust Clinician Research Training Fellowship. E.J. was supported by the Biotechnology and Biological Sciences Research Council. M.A.M.-T. is supported by an EMBO training fellowship. K.F. is supported by a studentship from Cancer Research UK (A19680). R.B. is supported by a studentship from the Science Without Borders Program (CAPES, Brazil). D.S. is a Cancer Research UK Career Development Fellow (reference C47648/A20837), and work in his laboratory is also supported by a Medical Research Council University grant to the MRC Human Genetics Unit. S.M.P. is a Cancer Research UK Senior Research Fellow (A17368)

LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells

Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signaling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence

The Dopamine Augmenter L-DOPA Does Not Affect Positive Mood in Healthy Human Volunteers

Dopamine neurotransmission influences approach toward rewards and reward-related cues. The best cited interpretation of this effect proposes that dopamine mediates the pleasure that commonly accompanies reward. This hypothesis has received support in some animal models and a few studies in humans. However, direct assessments of the effect of transiently increasing dopamine neurotransmission have been largely limited to the use of psychostimulant drugs, which elevate brain levels of multiple neurotransmitters in addition to dopamine. In the present study we tested the effect of more selectively elevating dopamine neurotransmission, as produced by administration of the immediate dopamine precursor, L-DOPA (0, 100/25, 200/50 mg, Sinemet), in healthy human volunteers. Neither dose altered positive mood. The results suggest that dopamine neurotransmission does not directly influence positive mood in humans

Necessary and sufficient conditions for the interchange between infimum and the symbol of integration

International audienc

Uso do laser, 670 nm, no quadro álgico de ratos submetidos à modelo experimental de ciatalgia Use of laser, 670 nm, in painful episodes of rats submitted to experimental model of sciatica

A ciatalgia deve-se a compressão do nervo isquiático em algum ponto de seu trajeto, e seu tratamento consiste em solucionar a causa da compressão nervosa, seja por tratamento cirúrgico ou conservador. Alguns recursos fisioterapêuticos atuam basicamente na redução dos sintomas ocasionados por este distúrbio. O objetivo deste estudo foi verificar a eficácia do laser 670 nm, em duas diferentes densidades de energia, na redução do quadro álgico, em ratos submetidos a modelo experimental de ciatalgia. Foram utilizados 18 ratos, divididos em 3 grupos: G1 (n=6) submetidos à ciatalgia e simulado o tratamento (grupo placebo), G2 (n=6) submetido à ciatalgia e tratados com laser 2 J/cm², G3 (n=6) submetidos à ciatalgia e irradiados com laser 4 J/cm². O nervo isquiático do membro posterior direito dos animais foi exposto e compressão com fio catgut em 4 pontos ao redor do nervo foi realizada. No 3° dia pós-operatório, iniciou-se o tratamento com laser na região do procedimento cirúrgico do membro posterior direito durante 10 dias consecutivos. Verificou-se por meio da marcha, o tempo em que o membro permanecia no ar nos períodos: anterior à ciatalgia, pré e pós-tratamento. Os resultados demonstraram que o laser não foi eficaz na redução do quadro álgico, porém com 4 J/cm² houve efeito positivo, sem restabelecimento completo da funcionalidade.<br>Sciatica is caused by the sciatic nerve compression in some point of its course, and its treatment consists of solving the nervous compression cause, either by surgical or conservative treatment. Some physiotherapeutic resources act basically in the reduction of the symptoms caused by this disturbance. The aim of this study was to verify the effectiveness of the laser 670 nm, in two different energy densities, in the pain reduction, in rats submitted to a sciatica experimental model. Eighteen rats, divided in 3 groups were used: G1 (n=6) submitted to sciatica and simulated treatment (placebo group), G2 (n=6) submitted to sciatica and treated with laser 2 J/cm², G3 (n=6) submitted to sciatica and irradiated with laser 4 J/cm². The hamstring nerve of the animals' right hind limb was exposed and compression with catgut thread in 4 points of the nerve was performed. On the 3rd post-operation day, the treatment was begun with laser in the surgical procedure area of the right hind limb for 10 days. The time during which the limb remained on the air was verified through gait in the following periods: previous to the sciatica, before and after treatment. The results have demonstrated that the laser was not effective in the pain reduction; however, with 4 J/cm² there was positive effect, without complete functionality reestablishment