Abstract A large genome-wide screen in patients with sporadic amyotrophic lateral sclerosis (ALS) showed that the common variant rs12608932 in gene UNC13A was associated with disease susceptibility. ...UNC13A regulates the release of neurotransmitters, including glutamate. Genetic risk factors that, in addition, modify survival, provide promising therapeutic targets in ALS, a disease whose etiology remains largely elusive. We examined whether UNC13A was associated with survival of ALS patients in a cohort of 450 sporadic ALS patients and 524 unaffected controls from a population-based study of ALS in The Netherlands. Additionally, survival data were collected from individuals of Dutch, Belgian, or Swedish descent (1767 cases, 1817 controls) who had participated in a previously published genome-wide association study of ALS. We related survival to rs12608932 genotype. In both cohorts, the minor allele of rs12608932 in UNC13A was not only associated with susceptibility but also with shorter survival of ALS patients. Our results further corroborate the role of UNC13A in ALS pathogenesis.
Mutations in FOXP1 have been linked to neurodevelopmental disorders including intellectual disability and autism; however, the underlying molecular mechanisms remain ill-defined. Here, we demonstrate ...with RNA and chromatin immunoprecipitation sequencing that FOXP1 directly regulates genes controlling neurogenesis. We show that FOXP1 is expressed in embryonic neural stem cells (NSCs), and modulation of FOXP1 expression affects both neuron and astrocyte differentiation. Using a murine model of cortical development, FOXP1-knockdown in utero was found to reduce NSC differentiation and migration during corticogenesis. Furthermore, transplantation of FOXP1-knockdown NSCs in neonatal mice after hypoxia-ischemia challenge demonstrated that FOXP1 is also required for neuronal differentiation and functionality in vivo. FOXP1 was found to repress the expression of Notch pathway genes including the Notch-ligand Jagged1, resulting in inhibition of Notch signaling. Finally, blockade of Jagged1 in FOXP1-knockdown NSCs rescued neuronal differentiation in vitro. Together, these data support a role for FOXP1 in regulating embryonic NSC differentiation by modulating Notch signaling.
•FOXP1 promotes astrocyte and neuronal differentiation of NSCs in vitro•FOXP1 promotes neuronal differentiation of NSCs in vivo•FOXP1 transcriptionally regulates pro-neural genes and represses Notch pathway genes•FOXP1 promotes neuronal differentiation by limiting Jagged1 expression
In this issue of Stem Cell Reports, Braccioli et al. describe how FOXP1 promotes embryonic neural stem cell differentiation both in vitro and in vivo by transcriptionally regulating pro-neural genes and by repressing the Notch-ligand Jagged1.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although genomewide association studies (GWAS) ...have advanced our understanding of the disease, the precise manner in which risk polymorphisms contribute to disease pathogenesis remains unclear. Of relevance, GWAS have shown that a polymorphism (rs12608932) in the
gene is associated with risk for both ALS and frontotemporal dementia (FTD). Homozygosity for the C-allele at rs12608932 modifies the ALS phenotype, as these patients are more likely to have bulbar-onset disease, cognitive impairment and FTD at baseline as well as shorter survival. UNC13A is expressed in neuronal tissue and is involved in maintaining synaptic active zones, by enabling the priming and docking of synaptic vesicles. In the absence of functional TDP-43, risk variants in
lead to the inclusion of a cryptic exon in
messenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion of
leads to impaired neurotransmission. Recent discoveries have identified
as a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate in
cases now underway and future approaches with antisense oligonucleotides currently under consideration. Considering
is a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery of
as a risk gene in ALS to the current therapeutic options being explored and how knowledge of its distinct phenotype needs to be taken into account in future trials.
The habenula is an evolutionarily conserved brain region comprising bilaterally paired nuclei that plays a key role in processing reward information and mediating aversive responses to negative ...stimuli. An important aspect underlying habenula function is relaying information between forebrain and mid- and hindbrain areas. This is mediated by its complex organization into multiple subdomains and corresponding complexity in circuit organization. Additionally, in many species habenular nuclei display left-right differences at the anatomical and functional level. In order to ensure proper functional organization of habenular circuitry, sophisticated molecular programs control the morphogenesis and wiring of the habenula during development. Knowledge of how these mechanisms shape the habenula is crucial for obtaining a complete understanding of this brain region and can provide invaluable tools to study habenula evolution and function. In this review we will discuss how these molecular mechanisms pattern the early embryonic nervous system and control the formation of the habenula, how they shape its asymmetric organization, and how these mechanisms ensure proper wiring of the habenular circuit. Finally, we will address unexplored aspects of habenula development and how these may direct future research.
•The habenula is an evolutionarily conserved brain region.•The habenular nuclei are asymmetrically organized into multiple subdomains.•The underlying neuronal circuit has a complex subdomain-specific organization pattern.•Habenula formation relies on mechanisms that pattern the early embryonic nervous system.•Multiple molecular pathways ensure proper subdomain-specific wiring of the habenulae.
Dopaminergic neurons located in the ventral midbrain (i.e. mesodiencephalic dopamine, mdDA, neurons) are essential for the control of diverse cognitive and motor behaviors and are associated with ...multiple psychiatric and neurodegenerative disorders. Three anatomically and functionally distinct subgroups of mdDA neurons have been identified (A8-A10) which give rise to prominent forebrain projections (i.e. the mesostriatal, mesocortical and mesolimbic pathways). The development of mdDA neurons is a complex, multi-step process. It includes early developmental events such as cell fate specification, differentiation and migration, and later events including neurite growth, guidance and pruning, and synapse formation. Significant progress has been made in defining the early events involved in mdDA neuron development see Smits, S.M., Burbach, J.P., Smidt, M.P., 2006. Developmental origin and fate of meso-diencephalic dopamine neurons. Prog. Neurobiol. 78, 1-16.. Although later stages of mdDA neuron development are less well understood, recent studies have begun to identify cellular and molecular signals thought to be involved in establishing mdDA neuronal connectivity. The purpose of the present review is to summarize our current understanding of the ontogeny and anatomy of mdDA axon pathways, to highlight recent progress in defining the cellular and molecular mechanisms that underlie the formation and remodeling of mdDA circuits, and to discuss the significance of this progress for understanding and treating situations of perturbed connectivity in the mdDA system.
Temporal lobe epilepsy is the most common drug-resistant form of epilepsy in adults. The reorganization of neural networks and the gene expression landscape underlying pathophysiologic network ...behavior in brain structures such as the hippocampus has been suggested to be controlled, in part, by microRNAs. To systematically assess their significance, we sequenced Argonaute-loaded microRNAs to define functionally engaged microRNAs in the hippocampus of three different animal models in two species and at six time points between the initial precipitating insult through to the establishment of chronic epilepsy. We then selected commonly up-regulated microRNAs for a functional in vivo therapeutic screen using oligonucleotide inhibitors. Argonaute sequencing generated 1.44 billion small RNA reads of which up to 82% were microRNAs, with over 400 unique microRNAs detected per model. Approximately half of the detected microRNAs were dysregulated in each epilepsy model. We prioritized commonly up-regulated microRNAs that were fully conserved in humans and designed custom antisense oligonucleotides for these candidate targets. Antiseizure phenotypes were observed upon knockdown of miR-10a-5p, miR-21a-5p, and miR-142a-5p and electrophysiological analyses indicated broad safety of this approach. Combined inhibition of these three microRNAs reduced spontaneous seizures in epileptic mice. Proteomic data, RNA sequencing, and pathway analysis on predicted and validated targets of these microRNAs implicated derepressed TGF-β signaling as a shared seizure-modifying mechanism. Correspondingly, inhibition of TGF-β signaling occluded the antiseizure effects of the antagomirs. Together, these results identify shared, dysregulated, and functionally active microRNAs during the pathogenesis of epilepsy which represent therapeutic antiseizure targets.
Abstract Mutations in the valosin-containing protein (VCP) gene were recently reported to be the cause of 1%–2% of familial amyotrophic lateral sclerosis (ALS) cases. VCP mutations are known to cause ...inclusion body myopathy (IBM) with Paget's disease (PDB) and frontotemporal dementia (FTD). The presence of VCP mutations in patients with sporadic ALS, sporadic ALS-FTD, and progressive muscular atrophy (PMA), a known clinical mimic of inclusion body myopathy, is not known. To determine the identity and frequency of VCP mutations we screened a cohort of 93 familial ALS, 754 sporadic ALS, 58 sporadic ALS-FTD, and 264 progressive muscular atrophy patients for mutations in the VCP gene. Two nonsynonymous mutations were detected; 1 known mutation (p.R159H) in a patient with familial ALS with several family members suffering from FTD, and 1 mutation (p.I114V) in a patient with sporadic ALS. Conservation analysis and protein prediction software indicate the p.I114V mutation to be a rare benign polymorphism. VCP mutations are a rare cause of familial ALS. The role of VCP mutations in sporadic ALS, if present, appears limited.
Mesodiencephalic dopamine neurons play central roles in the regulation of a wide range of brain functions, including voluntary movement and behavioral processes. These functions are served by ...distinct subtypes of mesodiencephalic dopamine neurons located in the substantia nigra pars compacta and the ventral tegmental area, which form the nigrostriatal, mesolimbic, and mesocortical pathways. Until now, mechanisms involved in dopaminergic circuit formation remained largely unknown. Here, we show that Lmx1a, Lmx1b, and Otx2 transcription factors control subtype-specific mesodiencephalic dopamine neurons and their appropriate axon innervation. Our results revealed that the expression of Plxnc1, an axon guidance receptor, is repressed by Lmx1a/b and enhanced by Otx2. We also found that Sema7a/Plxnc1 interactions are responsible for the segregation of nigrostriatal and mesolimbic dopaminergic pathways. These findings identify Lmx1a/b, Otx2, and Plxnc1 as determinants of dopaminergic circuit formation and should assist in engineering mesodiencephalic dopamine neurons capable of regenerating appropriate connections for cell therapy.Midbrain dopaminergic neurons (mDAs) in the VTA and SNpc project to different regions and form distinct circuits. Here the authors show that transcription factors Lmx1a, Lmx1b, and Otx2 control the axon guidance of mDAs and the segregation of mesolimbic and nigrostriatal dopaminergic pathways.
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