Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mTOR-related epilepsy.

Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII results from somatic mosaicism due to post-zygotic mutations in genes of the PI3K-AKT-mTOR pathway, which produce a subset of dysmorphic cells clustered within healthy brain tissue. Here we show a correlation between epileptiform activity in acute cortical slices obtained from human surgical FCDII brain tissues and the density of dysmorphic neurons.

Hippocampal and neocortical BRAF mutant non-expansive lesions in focal epilepsies.

Objective: Mesial Temporal Lobe Epilepsy-associated Hippocampal Sclerosis (MTLE-HS) is a syndrome associated with various aetiologies. We previously identified CD34-positive extravascular stellate cells (CD34+ cells) possibly related to BRAF oncogenic variant in a subset of MTLE-HS. We aimed to identify the BRAF oncogenic variants and characterise the CD34+ cells.

Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, yet it remains refractory to systemic therapy. Elimination of senescent cells has emerged as a promising new treatment approach against cancer. Here, we investigated the contribution of senescent cells to GBM progression.

A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas.

Chordoid glioma (ChG) is a characteristic, slow growing, and well-circumscribed diencephalic tumor, whose mutational landscape is unknown. Here we report the analysis of 16 ChG by whole-exome and RNA-sequencing. We found that 15 ChG harbor the same PRKCA mutation.

Injury-Induced Senescence Enables In Vivo Reprogramming in Skeletal Muscle.

In vivo reprogramming is a promising approach for tissue regeneration in response to injury. Several examples of in vivo reprogramming have been reported in a variety of lineages, but some including skeletal muscle have so far proven refractory. Here, we show that acute and chronic injury enables transcription-factor-mediated reprogramming in skeletal muscle.

Numb is required to prevent p53-dependent senescence following skeletal muscle injury.

Regeneration relies on coordinated action of multiple cell types to reconstitute the damaged tissue. Here we inactivate the endocytic adaptor protein Numb in skeletal muscle stem cells prior to chronic or severe muscle injury in mice. We observe two types of senescence in regenerating muscle; a transient senescence in non-myogenic cells of control and Numb mutant mice that partly depends on INK4a/ARF activity, and a persistent senescence in myogenic cells lacking Numb.

Embryonic founders of adult muscle stem cells are primed by the determination gene Mrf4.

Skeletal muscle satellite cells play a critical role during muscle growth, homoeostasis and regeneration. Selective induction of the muscle determination genes Myf5, Myod and Mrf4 during prenatal development can potentially impact on the reported functional heterogeneity of adult satellite cells. Accordingly, expression of Myf5 was reported to diminish the self-renewal potential of the majority of satellite cells.

Numb promotes an increase in skeletal muscle progenitor cells in the embryonic somite.

Multiple cell types arise from cells in the dermomyotome of the somite that express Pax3 and Pax7, and myogenesis is regulated by Notch signaling. The asymmetric cell fate determinant Numb is thought to promote differentiation of skeletal muscle and other lineages by negatively regulating Notch signaling. We used transgenesis to overexpress Numb spatiotemporally in Pax3(+)/Pax7(+) somitic stem and progenitor cells in mouse embryos using a spatiotemporally regulated enhancer element from the Myf5 locus that can target muscle progenitor cells prior to cell commitment.

Early mouse caudal development relies on crosstalk between retinoic acid, Shh and Fgf signalling pathways.

The progressive generation of embryonic trunk structures relies on the proper patterning of the caudal epiblast, which involves the integration of several signalling pathways. We have investigated the function of retinoic acid (RA) signalling during this process. We show that, in addition to posterior mesendoderm, primitive streak and node cells transiently express the RA-synthesizing enzyme Raldh2 prior to the headfold stage.

Combinatorial signalling controls Neurogenin2 expression at the onset of spinal neurogenesis.

A central issue during embryonic development is to define how different signals cooperate in generating unique cell types. To address this issue, we focused on the function and the regulation of the proneural gene Neurogenin2 (Neurog2) during early mouse spinal neurogenesis. We showed that Neurog2 is first expressed in cells within the neural plate anterior to the node from the 5 somite-stage.

Asymmetric cell divisions and asymmetric cell fates.

The regulation of self-renewal, cell diversity, and differentiation can occur by modulating symmetric and asymmetric cell divisions. Remarkably, asymmetric cell divisions can arise through multiple processes in which molecules in the cytoplasm and nucleus, as well as template "immortal" DNA strands, can segregate to one daughter cell during cell division. Explaining how these events direct distinct daughter cell fates is a major challenge to understanding how the organism is assembled and maintained for a lifetime.

Retinaldehyde dehydrogenase 2 and Hoxc8 are required in the murine brachial spinal cord for the specification of Lim1+ motoneurons and the correct distribution of Islet1+ motoneurons.

Retinoic acid (RA) activity plays sequential roles during the development of the ventral spinal cord. Here, we have investigated the functions of local RA synthesis in the process of motoneuron specification and early differentiation using a conditional knockout strategy that ablates the function of the retinaldehyde dehydrogenase 2 (Raldh2) synthesizing enzyme essentially in brachial motoneurons, and later in mesenchymal cells at the base of the forelimb. Mutant (Raldh2L-/-) embryos display an early embryonic loss of a subset of Lim1+ brachial motoneurons, a mispositioning of Islet1+ neurons and inappropriate axonal projections of one of the nerves innervating extensor limb muscles, which lead to an adult forepaw neuromuscular defect.

Stat3 signaling is present and active during development of the central nervous system and eye of vertebrates.

Stat3, a member of the signal transducer and activator of transcription (STAT) family, plays a central role in mediating cell growth, differentiation, and survival signals. In this report, we show that Stat3 immunoreactivity was localized to specific regions in the developing mouse brain, neural tube, and eye from embryonic day 10.5 to postnatal day 0.

Direct and concentration-dependent regulation of the proneural gene Neurogenin2 by Pax6.

Expression of the proneural gene Neurogenin2 is controlled by several enhancer elements, with the E1 element active in restricted progenitor domains in the embryonic spinal cord and telencephalon that express the homeodomain protein Pax6. We show that Pax6 function is both required and sufficient to activate this enhancer, and we identify one evolutionary conserved sequence in the E1 element with high similarity to a consensus Pax6 binding site. This conserved sequence binds Pax6 protein with low affinity both in vitro and in vivo, and its disruption results in a severe decrease in E1 activity in the spinal cord and in its abolition in the cerebral cortex.

Notch activity is required to maintain floorplate identity and to control neurogenesis in the chick hindbrain and spinal cord.

Notch signalling plays a major role in many invertebrate and vertebrate patterning systems. In this paper, we use high-titre, non-replicative pseudotype viruses to show that the two Notch ligands, Delta1 and Serrate1 (Jagged1), have differing activities in the developing chick spinal cord and hindbrain. In the walls of the neural tube, Serrate1 appears not to affect neurogenesis, in contrast to Delta1 which mediates lateral inhibition as elsewhere in the nervous system.

The regional pattern of retinoic acid synthesis by RALDH2 is essential for the development of posterior pharyngeal arches and the enteric nervous system.

Targeted inactivation of the mouse retinaldehyde dehydrogenase 2 (RALDH2/ALDH1a2), the enzyme responsible for early embryonic retinoic acid synthesis, is embryonic lethal because of defects in early heart morphogenesis. Transient maternal RA supplementation from E7.5 to (at least) E8.

A floor plate enhancer of the zebrafish netrin1 gene requires Cyclops (Nodal) signalling and the winged helix transcription factor FoxA2.

The floor plate is an organising centre that controls neural differentiation and axonogenesis in the neural tube. The axon guidance molecule Netrin1 is expressed in the floor plate of zebrafish embryos. To elucidate the regulatory mechanisms underlying expression in the floor plate, we scanned the netrin1 locus for regulatory regions and identified an enhancer that drives expression in the floor plate and hypochord of transgenic embryos.