The Emerging Biology of Autism Spectrum Disorders State, Matthew W.; Šestan, Nenad
Science (American Association for the Advancement of Science),
09/2012, Letnik:
337, Številka:
6100
Journal Article
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Expression patterns of the diverse genes disrupted in autism spectrum disorders in the developing brain give a fresh perspective on the underlying biology.
Autism spectrum disorders (ASD) are a ...genetically and phenotypically heterogeneous group of syndromes defined by fundamental impairments in social reciprocity and language development accompanied by highly restrictive interests and/or repetitive behaviors. Recent advances in genetics, genomics, developmental neurobiology, systems biology, monogenic neurodevelopment syndromes, and induced pluripotent stem cells (iPSC) are now offering remarkable insights into their etiologies and converging to provide a clear and immediate path forward from the bench to the bedside.
The cerebral neocortex is segregated into six horizontal layers, each containing unique populations of molecularly and functionally distinct excitatory projection (pyramidal) neurons and inhibitory ...interneurons. Development of the neocortex requires the orchestrated execution of a series of crucial processes, including the migration of young neurons into appropriate positions within the nascent neocortex, and the acquisition of layer-specific neuronal identities and axonal projections. Here, we discuss emerging evidence supporting the notion that the migration and final laminar positioning of cortical neurons are also co-regulated by cell type- and layer-specific transcription factors that play concomitant roles in determining the molecular identity and axonal connectivity of these neurons. These transcriptional programs thus provide direct links between the mechanisms controlling the laminar position and identity of cortical neurons.
The co-emergence of a six-layered cerebral neocortex and its corticospinal output system is one of the evolutionary hallmarks of mammals. However, the genetic programs that underlie their development ...and evolution remain poorly understood. Here we identify a conserved non-exonic element (E4) that acts as a cortex-specific enhancer for the nearby gene Fezf2 (also known as Fezl and Zfp312), which is required for the specification of corticospinal neuron identity and connectivity. We find that SOX4 and SOX11 functionally compete with the repressor SOX5 in the transactivation of E4. Cortex-specific double deletion of Sox4 and Sox11 leads to the loss of Fezf2 expression, failed specification of corticospinal neurons and, independent of Fezf2, a reeler-like inversion of layers. We show evidence supporting the emergence of functional SOX-binding sites in E4 during tetrapod evolution, and their subsequent stabilization in mammals and possibly amniotes. These findings reveal that SOX transcription factors converge onto a cis-acting element of Fezf2 and form critical components of a regulatory network controlling the identity and connectivity of corticospinal neurons.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Brain development and function depend on the precise regulation of gene expression. However, our understanding of the complexity and dynamics of the transcriptome of the human brain is incomplete. ...Here we report the generation and analysis of exon-level transcriptome and associated genotyping data, representing males and females of different ethnicities, from multiple brain regions and neocortical areas of developing and adult post-mortem human brains. We found that 86 per cent of the genes analysed were expressed, and that 90 per cent of these were differentially regulated at the whole-transcript or exon level across brain regions and/or time. The majority of these spatio-temporal differences were detected before birth, with subsequent increases in the similarity among regional transcriptomes. The transcriptome is organized into distinct co-expression networks, and shows sex-biased gene expression and exon usage. We also profiled trajectories of genes associated with neurobiological categories and diseases, and identified associations between single nucleotide polymorphisms and gene expression. This study provides a comprehensive data set on the human brain transcriptome and insights into the transcriptional foundations of human neurodevelopment.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Adolescent mental health—Opportunity and obligation Lee, Francis S.; Heimer, Hakon; Giedd, Jay N. ...
Science (American Association for the Advancement of Science),
10/2014, Letnik:
346, Številka:
6209
Journal Article
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Emerging neuroscience offers hope for treatments
The adolescent brain is more “plastic” than it will ever be again, capable of remarkable adaptability in light of the many social, physical, sexual, ...and intellectual challenges that this developmental phase brings. This is also a peak time for clinical onset of most mental illnesses (see the chart) (
1
). One in five adolescents have a mental illness that will persist into adulthood (
2
). Mental illnesses that emerge before adulthood impose a 10-fold higher cost than those that emerge later in life (
3
). Mental health costs are the highest single source of global economic burden in the world (
4
).
The lifelong addition of neurons to the hippocampus is a remarkable form of structural plasticity, yet the molecular controls over proliferation, neuronal fate determination, survival, and maturation ...are poorly understood. Expression of Notch1 was found to change dynamically depending on the differentiation state of neural precursor cells. Through the use of inducible gain- and loss-of-function of Notch1 mice we show that this membrane receptor is essential to these distinct processes. We found in vivo that activated Notch1 overexpression induces proliferation, whereas γ-secretase inhibition or genetic ablation of Notch1 promotes cell cycle exit, indicating that the level of activated Notch1 regulates the magnitude of neurogenesis from postnatal progenitor cells. Abrogation of Notch signaling in vivo or in vitro leads to a transition from neural stem or precursor cells to transit-amplifying cells or neurons. Further, genetic Notch1 manipulation modulates survival and dendritic morphology of newborn granule cells. These results provide evidence for the expansive prevalence of Notch signaling in hippocampal morphogenesis and plasticity, suggesting that Notch1 could be a target of diverse traumatic and environmental modulators of adult neurogenesis.
The cerebral cortex constitutes more than half the volume of the human brain and is presumed to be responsible for the neuronal computations underlying complex phenomena, such as perception, thought, ...language, attention, episodic memory and voluntary movement. Rodent models are extremely valuable for the investigation of brain development, but cannot provide insight into aspects that are unique or highly derived in humans. Many human psychiatric and neurological conditions have developmental origins but cannot be studied adequately in animal models. The human cerebral cortex has some unique genetic, molecular, cellular and anatomical features, which need to be further explored. The Anatomical Society devoted its summer meeting to the topic of Human Brain Development in June 2018 to tackle these important issues. The meeting was organized by Gavin Clowry (Newcastle University) and Zoltán Molnár (University of Oxford), and held at St John's College, Oxford. The participants provided a broad overview of the structure of the human brain in the context of scaling relationships across the brains of mammals, conserved principles and recent changes in the human lineage. Speakers considered how neuronal progenitors diversified in human to generate an increasing variety of cortical neurons. The formation of the earliest cortical circuits of the earliest generated neurons in the subplate was discussed together with their involvement in neurodevelopmental pathologies. Gene expression networks and susceptibility genes associated to neurodevelopmental diseases were discussed and compared with the networks that can be identified in organoids developed from induced pluripotent stem cells that recapitulate some aspects of in vivo development. New views were discussed on the specification of glutamatergic pyramidal and γ‐aminobutyric acid (GABA)ergic interneurons. With the advancement of various in vivo imaging methods, the histopathological observations can be now linked to in vivo normal conditions and to various diseases. Our review gives a general evaluation of the exciting new developments in these areas. The human cortex has a much enlarged association cortex with greater interconnectivity of cortical areas with each other and with an expanded thalamus. The human cortex has relative enlargement of the upper layers, enhanced diversity and function of inhibitory interneurons and a highly expanded transient subplate layer during development. Here we highlight recent studies that address how these differences emerge during development focusing on diverse facets of our evolution.
This review explores the unique genetic, molecular, cellular and anatomical features of the developing human cerebral cortex. For instance, in both mouse and human, expression of transcription factors SP8 and COUPTFII forms a protomap in the cortical ventricular zone, but in human, the SP8+ territory extends throughout parietal and occipital cortex and the COUPTFII+ territory is expanded reflecting the relative enlargement of the temporal cortex. Ventral telencephalon COUP‐TFII expression reveals an expanded caudal ganglionic eminence, origin of cortical inhibitory interneuron subtypes found in greater relative abundance in human.
Whether cortical projection neurons (CPNs) are generated by multipotent or fate-restricted progenitors is not completely understood. In this issue of Neuron, Guo et al. (2013) provide evidence that ...mouse Fezf2-expressing radial glial cells are multipotent progenitors that sequentially generate all major CPN subtypes and glia.
MicroRNAs (miRNAs) are short RNA gene regulators typically produced from primary transcripts that are cleaved by the nuclear microprocessor complex, with the resulting precursor miRNA hairpins ...exported by exportin 5 and processed by cytoplasmic Dicer to yield two (5p and 3p) miRNAs. Here, we document microprocessor-independent 7-methylguanosine (m7G)-capped pre-miRNAs, whose 5′ ends coincide with transcription start sites and 3′ ends are most likely generated by transcription termination. By establishing a small RNA Cap-seq method that employs the cap-binding protein eIF4E, we identified a group of murine m7G-capped pre-miRNAs genome wide. The m7G-capped pre-miRNAs are exported via the PHAX-exportin 1 pathway. After Dicer cleavage, only the 3p-miRNA is efficiently loaded onto Argonaute to form a functional microRNP. This unusual miRNA biogenesis pathway, which differs in pre-miRNA synthesis, nuclear-cytoplasmic transport, and guide strand selection, enables the development of shRNA expression constructs that produce a single 3p-siRNA.
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•Microprocessor-independent Dicer-dependent 5′ m7G-capped pre-miRNAs are identified•The 5′ and 3′ ends of m7G-capped pre-miRNAs are generated directly by transcription•Exportin 1 exports m7G-capped pre-miRNAs•m7G-capped shRNA expression vectors express a single siRNA
A microprocessor-independent pathway distinct from canonical miRNA biogenesis generates 7-methylguanosine (m7G)-capped pre-miRNAs whose 5′ ends coincide with transcription start sites.
The exuberant growth of neurites during development becomes markedly reduced as cortical neurons mature. In vitro studies of neurons from mouse cerebral cortex revealed that contact-mediated Notch ...signaling regulates the capacity of neurons to extend and elaborate neurites. Up-regulation of Notch activity was concomitant with an increase in the number of interneuronal contacts and cessation of neurite growth. In neurons with low Notch activity, which readily extend neurites, up-regulation of Notch activity either inhibited extension or caused retraction of neurites. Conversely, in more mature neurons that had ceased their growth after establishing numerous connections and displayed high Notch activity, inhibition of Notch signaling promoted neurite extension. Thus, the formation of neuronal contacts results in activation of Notch receptors, leading to restriction of neuronal growth and a subsequent arrest in maturity.
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