Cytomegalic parvalbumin neurons in fetal cases of hemimegalencephaly.

Objective: Mutations in genes of the mTOR pathway have been identified as a major cause of hemimegalencephaly (HMG), focal cortical dysplasia type II, and tuberous sclerosis, cortical malformations associated with epilepsy. These conditions are characterized at the cellular level by increased size of pyramidal neurons that grow with dysmorphic features and in some cases by the presence of giant balloon cells. Our previous research in tuberous sclerosis has shown that parvalbumin (Pvalb) and calbindin immunoreactive cells in cortical and subcortical tuberal lesions show cytomegalic features, suggesting the involvement of GABAergic cells in mTOR-related pathologies.

FLNA regulates neuronal maturation by modulating RAC1-Cofilin activity in the developing cortex.

Periventricular nodular heterotopia (PNH), the most common brain malformation diagnosed in adulthood, is characterized by the presence of neuronal nodules along the ventricular walls. PNH is mainly associated with mutations in the FLNA gene - encoding an actin-binding protein - and patients often develop epilepsy. However, the molecular mechanisms underlying the neuronal failure still remain elusive.

Dendritic Spine Plasticity: Function and Mechanisms.

Dendritic spines are small protrusions studding neuronal dendrites, first described in 1888 by Ramón y Cajal using his famous Golgi stainings. Around 50 years later the advance of electron microscopy (EM) confirmed Cajal's intuition that spines constitute the postsynaptic site of most excitatory synapses in the mammalian brain. The finding that spine density decreases between young and adult ages in fixed tissues suggested that spines are dynamic.

Single cell RNA sequencing identifies early diversity of sensory neurons forming via bi-potential intermediates.

Somatic sensation is defined by the existence of a diversity of primary sensory neurons with unique biological features and response profiles to external and internal stimuli. However, there is no coherent picture about how this diversity of cell states is transcriptionally generated. Here, we use deep single cell analysis to resolve fate splits and molecular biasing processes during sensory neurogenesis in mice.

Disorders of neurogenesis and cortical development.

The development of the cerebral cortex requires complex sequential processes that have to be precisely orchestrated. The localization and timing of neuronal progenitor proliferation and of neuronal migration define the identity, laminar positioning, and specific connectivity of each single cortical neuron. Alterations at any step of this organized series of events-due to genetic mutations or environmental factors-lead to defined brain pathologies collectively known as malformations of cortical development (MCDs), which are now recognized as a leading cause of drug-resistant epilepsy and intellectual disability.

Direct and efficient transfection of mouse neural stem cells and mature neurons by mRNA electroporation.

brain electroporation of DNA expression vectors is a widely used method for lineage and gene function studies in the developing and postnatal brain. However, transfection efficiency of DNA is limited and adult brain tissue is refractory to electroporation. Here, we present a systematic study of mRNA as a vector for acute genetic manipulation in the developing and adult brain.

Zic-Proteins Are Repressors of Dopaminergic Forebrain Fate in Mice and .

In the postnatal forebrain regionalized neural stem cells along the ventricular walls produce olfactory bulb (OB) interneurons with varying neurotransmitter phenotypes and positions. To understand the molecular basis of this region-specific variability we analyzed gene expression in the postnatal dorsal and lateral lineages in mice of both sexes from stem cells to neurons. We show that both lineages maintain transcription factor signatures of their embryonic site of origin, the pallium and subpallium.

miR-200 family controls late steps of postnatal forebrain neurogenesis via Zeb2 inhibition.

During neurogenesis, generation, migration and integration of the correct numbers of each neuron sub-type depends on complex molecular interactions in space and time. MicroRNAs represent a key control level allowing the flexibility and stability needed for this process. Insight into the role of this regulatory pathway in the brain is still limited.

Reducing glypican-4 in ES cells improves recovery in a rat model of Parkinson's disease by increasing the production of dopaminergic neurons and decreasing teratoma formation.

The heparan sulfate proteoglycan Glypican 4 (Gpc4) is strongly expressed in mouse embryonic stem (ES) cells where it controls the maintenance of self-renewal by modulating Wnt/β-catenin signaling activities. Here we show that mouse ES cells carrying a hypomorphic Gpc4 allele, in a single-step neuronal differentiation protocol, show increased differentiation into dopaminergic neurons expressing tyrosine hydroxylase (TH) and nuclear receptor related-1 protein (Nurr1) 1. In contrast to wild-type cells, these differentiating Gpc4-mutant cells expressed high levels of DOPA decarboxylase and the dopamine transporter, two markers expressed by fully mature dopaminergic neurons.

Modulating Glypican4 suppresses tumorigenicity of embryonic stem cells while preserving self-renewal and pluripotency.

Self-renewal and differentiation of stem cell depend on a dynamic interplay of cell-extrinsic and -intrinsic regulators. However, how stem cells perceive the right amount of signal and at the right time to undergo a precise developmental program remains poorly understood. The cell surface proteins Glypicans act as gatekeepers of environmental signals to modulate their perception by target cells.

miR-7a regulation of Pax6 controls spatial origin of forebrain dopaminergic neurons.

In the postnatal and adult mouse forebrain, a mosaic of spatially separated neural stem cells along the lateral wall of the ventricles generates defined types of olfactory bulb neurons. To understand the mechanisms underlying the regionalization of the stem cell pool, we focused on the transcription factor Pax6, a determinant of the dopaminergic phenotype in this system. We found that, although Pax6 mRNA was transcribed widely along the ventricular walls, Pax6 protein was restricted to the dorsal aspect.

High transfection efficiency of neural stem cells with magnetofection.

Primary neural stem cells (NSCs) can be cultivated and differentiated in vitro but are difficult to transfect using conventional methods. We describe a simple and rapid magnetofection-based method suitable for the lab bench as well as for high-throughput projects. Our method yields high transfection efficiency and can be used for deciphering the genetic control of neural cell differentiation.

NeuroD1 induces terminal neuronal differentiation in olfactory neurogenesis.

After their generation and specification in periventricular regions, neuronal precursors maintain an immature and migratory state until their arrival in the respective target structures. Only here are terminal differentiation and synaptic integration induced. Although the molecular control of neuronal specification has started to be elucidated, little is known about the factors that control the latest maturation steps.

Fate mapping and lineage analyses demonstrate the production of a large number of striatal neuroblasts after transforming growth factor alpha and noggin striatal infusions into the dopamine-depleted striatum.

Infusion of transforming growth factor alpha (TGFalpha) into the adult dopamine (DA)-depleted striatum generates a local population of nestin(+)/proliferating cell nuclear antigen (PCNA)(+) newborn cells. The precise origin and fate of these new striatal cells are unknown, making it difficult to direct them for neural repair in Parkinson's disease. Experiments in rats using 5-bromo-2'-deoxyuridine (BrdU) to label neural progenitor cells showed that during TGFalpha infusion in the DA-depleted striatum, newborn striatal cells formed a homogeneous population of precursors, with the majority coexpressing nestin, Mash1, Olig2, and epidermal growth factor receptor, consistent with the phenotype of multipotent C cells.

[Olfactory bulb neurogenesis and its neurological impact].

Contrary to the long-held dogma according to which the adult mammalian brain does not produce neurons anymore, neuronal turnover has been reported in two discrete areas of the adult brain: the hippocampus and the olfactory bulb. Adult-generated neurons are produced from neural stem cells located in the hippocampal subgranular zone and the subventricular zone of the lateral ventricles. Recently, number of genetic and epigenetic factors that modulate proliferation of stem cells, migration, differentiation and survival of newborn neurons have been characterized.

Delayed onset of odor detection in neonatal mice lacking tenascin-C.

The olfactory bulb is one of the few regions in the adult mammalian forebrain in which neurons are constitutively replaced throughout life. New neurons generated in the subventricular zone migrate long distances along the rostral migratory stream to the olfactory bulb where they differentiate into interneurons. Neuronal precursor generation, migration and incorporation into the bulbar network occur in an environment rich in extracellular matrix molecules.

Neuronal fate determinants of adult olfactory bulb neurogenesis.

Adult neurogenesis in mammals is restricted to two small regions, including the olfactory bulb, where GABAergic and dopaminergic interneurons are newly generated throughout the entire lifespan. However, the mechanisms directing them towards a specific neuronal phenotype are not yet understood. Here, we demonstrate the dual role of the transcription factor Pax6 in generating neuronal progenitors and also in directing them towards a dopaminergic periglomerular phenotype in adult mice.

Local neurons play key roles in the mammalian olfactory bulb.

Over the past few decades, research exploring how the brain perceives, discriminates, and recognizes odorant molecules has received a growing interest. Today, olfaction is no longer considered a matter of poetry. Chemical senses entered the biological era when an increasing number of scientists started to elucidate the early stages of the olfactory pathway.

Tenascin-R mediates activity-dependent recruitment of neuroblasts in the adult mouse forebrain.

Neuroblasts arising in the adult forebrain that travel to the olfactory bulb use two modes of migration: tangentially, along the rostral migratory stream, and radially, in the core of the olfactory bulb where they start to ascend to the outer layers. Although the mechanisms of tangential migration have been extensively studied, the factors controlling radial migration remain unexplored. Here we report that the extracellular matrix glycoprotein tenascin-R, expressed in the adult mouse olfactory bulb, initiates both the detachment of neuroblasts from chains and their radial migration.