583 research outputs found
Post-zygotic brain mosaicism as a result of partial reversion of pre-zygotic aneuploidy
No full textBrain somatic mosaicism is linked to several neurological disorders, thought to arise post-zygotically. The recent study by Miller et al. suggests prezygotic aneuploidy followed by postzygotic partial reversion leads to a recurrent form of brain mosaicism-related epilepsy
A comparative view of human and mouse telencephalon inhibitory neuron development
No full textHuman GABAergic inhibitory neurons (INs) in the telencephalon play crucial roles in modulating neural circuits, generating cortical oscillations, and maintaining the balance between excitation and inhibition. The major IN subtypes are based on their gene expression profiles, morphological diversity and circuit-specific functions. Although previous foundational work has established that INs originate in the ganglionic eminence regions in mice, recent studies have questioned origins in humans and non-human primates. We review the origins of INs in mice and compare with recent findings from primary human prenatal brain tissue culture experiments and lineage analysis from somatic variants in neurotypical human cadavers and human brain organoids. Together, these studies suggest potential primate- or human-specific processes that may have been overlooked in mouse models and could have implications for brain disorders.
Primary cilia in neurodevelopmental disorders.
No full textPrimary cilia are generally solitary organelles that emanate from the surface of almost all vertebrate cell types. Until recently, details regarding the function of these structures were lacking; however, extensive evidence now suggests that primary cilia have critical roles in sensing the extracellular environment, and in coordinating developmental and homeostatic signalling pathways. Furthermore, disruption of these functions seems to underlie a diverse spectrum of disorders, known as primary ciliopathies. These disorders are characterized by wide-ranging clinical and genetic heterogeneity, but with substantial overlap among distinct conditions. Indeed, ciliopathies are associated with a large variety of manifestations that often include distinctive neurological findings. Herein, we review neurological features associated with primary ciliopathies, highlight genotype-phenotype correlations, and discuss potential mechanisms underlying these findings
The ciliary proteins Meckelin and Jouberin are required for retinoic acid-dependent neural differentiation of mouse embryonic stem cells
No full textThe dysfunction of the primary cilium, a complex, evolutionarily conserved, organelle playing an important role in sensing and transducing cell signals, is the unifying pathogenetic mechanism of a growing number of diseases collectively termed "ciliopathies", typically characterized by multiorgan involvement. Developmental defects of the central nervous system (CNS) characterize a subset of ciliopathies showing clinical and genetic overlap, such as Joubert syndrome (jS) and Meckel syndrome (MS). Although several knock-out mice lacking a variety of ciliary proteins have shown the importance of primary cilia in the development of the brain and CNS-derived structures, developmental in vitro studies, extremely useful to unravel the role of primary cilia along the course of neural differentiation, are still missing. Mouse embryonic stem cells (mESCs) have been recently proven to mimic brain development, giving the unique opportunity to dissect the CNS differentiation process along its sequential steps. In the present study we show that mESCs express the ciliary proteins Meckelin and Jouberin in a developmentally-regulated manner, and that these proteins co-localize with acetylated tubulin labeled cilia located at the outer embryonic layer. Further, mESCs differentiating along the neuronal lineage activate the cilia-dependent sonic hedgehog signaling machinery, which is impaired in Meckelin knockout cells but results unaffected in Jouberin-deficient mESCs. However, both lose the ability to acquire a neuronal phenotype. Altogether, these results demonstrate a pivotal rob' of Meckelin and Jouberin during embryonic neural specification and indicate mESCs as a suitable tool to investigate the developmental impact of ciliary proteins dysfunction. (C) 2014 International Society of Differentiation. Published by Elsevier B.V. All rights reserved
For Peter
No full textPart of the Yangai Broadside IV Series.Signed by the author and illustrator. Numbered G / 30
'To live and die [for] Dixie': Irish civilians and the Confederate States of America
No full textAround 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism
PAK3 mutation in nonsyndromic X-linked mental retardation
No full textNonsyndromic X-linked mental retardation (MRX) syndromes are clinically homogeneous but genetically heterogeneous disorders, whose genetic bases are largely unknown. Affected individuals in a multiplex pedigree with MRX (MRX30), previously mapped to Xq22, show a point mutation in the PAK3 (p21-activated kinase) gene, which encodes a serine-threonine kinase. PAK proteins are crucial effectors linking Rho GTPases to cytoskeletal reorganization and to nuclear signalling. The mutation produces premature termination, disrupting kinase function. MRI analysis showed no gross defects in brain development. Immunofluorescence analysis showed that PAK3 protein is highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus. Signal transduction through Rho GTPases and PAK3 may be critical for human cognitive function.Kristina M. Allen ; Joseph G. Gleeson ; Shubha Bagrodia ; Michael W. Partington ; John C. Macmillan ; Richard A. Cerione ; John C. Mulley ; Christopher A. Wals
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Elucidating the Genetic and Molecular Mechanisms of Recessive Pediatric Brain Disease
No full textThe structural organization and maturation of the brain are the result of a precisely orchestrated series of developmental processes with complex genetic regulation that occur during embryonic gestation and are critical for neuronal identity, wiring and connectivity. Mutations affecting any of the cellular processes involved in proper human brain development can lead to altered neurodevelopment and result in a number of different neurological diseases. Such diseases arising as a consequence of a biallelic mutation in a single gene are much more prevalent among offspring of consanguineous marriages, increasing the odds that a deleterious mutation will be inherited on both chromosomes. The identification of a disease-causing gene in families with inherited brain disorders is one of the most useful methods for gaining insight into human brain development, function, and pathology. This study largely focuses on identifying novel mutations in both known and novel recessive pediatric brain diseases using next-generation sequencing approaches in combination with in vitro and in vivo modeling. By taking advantage of the large number of consanguineous families in our cohort, we are not only able to explore the cause of disease directly in humans, but also able to determine genetic disease risk and identify novel disease-causing variants with a high level of certainty. A total of 88 affected individuals were identified and studied from 46 families displaying a range of SBDs including neurodegeneration (i.e. cortical and cerebellar atrophy), microlissencephaly, PCH, and Joubert syndrome, among other symptoms. A total of six disease-causing genes, ADPRHL2, TMX2, TRAPPC4, HEATR5B, HPDL, and ARMC9 were identified, four of which had never been implicated in disease prior to this study. We were further able to model disease in vivo for three out of the five genes (ADPRHL2, HEATR5B, and HPDL) using either fly or mouse models. Taken together, this study not only provides further knowledge in identifying novel causes of both previously unknown diseases as well as known diseases with unknown cause, but also provides further promise to the application of NGS in revealing the full spectrum of mutations associated with these diseases and in further delineating the relevant molecular pathways involved
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Antisense Oligonucleotide Treatment for Focal Malformations of Cortical Development
No full textFocal Malformations of Cortical Development (FMCD) are neurological developmental disorders that are a major cause of drug-resistant pediatric epilepsy. Along with seizures, patients display disrupted cortical architecture and neuronal organization. Current treatment involves invasive surgical resection of the epileptic focus, which may only show partial benefit. Recent studies have identified several categories of post-zygotic somatic mutations that cause FMCD, however this effort has not yet been utilized to generate therapies. Antisense oligonucleotides (ASOs) are safe, stable and programmable molecules that can be designed to target specific mutations such as those that cause FMCD. To demonstrate the therapeutic potential of ASOs against FMCD, we introduced AKT3E17K, an FMCD causing variant in mice brain and subsequently treated them with ASOs designed to silence the toxic gene. The ASO treatment was able to rescue cortical architecture. Later studies may explore the dependency of treatment on the stage of the disease, the dose of the drug, and the type of FMCD causing mutations. Successful development of ASO therapy can provide safe, effective and non-invasive treatment for FMCD
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