scholarly journals An allelic series of spontaneous mutations in Rorb cause a gait phenotype, retinal abnormalities, and transcriptomic changes relevant to human neurodevelopmental conditions

2021 ◽  
Author(s):  
George C Murray ◽  
Jason Bubier ◽  
Oraya J Zinder ◽  
Belinda Harris ◽  
James Clark ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Nervous System ◽  
Cell Fate ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Orphan Receptor ◽  
Mouse Strains ◽  
Spontaneous Mutations ◽  
Allelic Series ◽  
Neurological Conditions

Rorb encodes the Retinoic Acid Receptor-related orphan receptor beta. Mutations in either of the two transcripts of Rorb cause defects in multiple systems, including abnormal photoreceptor abundance and morphology in the retina and a characteristic high-stepper or duck-like gait arising from dysfunction of interneurons in the spinal cord. Rorb is also important for cortical development and cell fate specification in mice. Rorb variants segregate with epilepsy and comorbidities such as intellectual disability in numerous clinical cases. Here we describe five mouse strains with spontaneous mutations in Rorb identified by their gait phenotype. These mutations affect different domains and isoforms of Rorb, which correspond to the spectrum of anatomical and physiological phenotypes exhibited by these mice. Gene set analysis in Rorb mutants implicates pathways associated with development and nervous system function, and differential gene expression analysis indicates changes in numerous genes related to epilepsy, bipolar disorder, and autism spectrum disorder (ASD). Many of these genes and their protein products are known to interact during synapse formation and neuronal activity. These findings further illuminate the role of Rorb in nervous system development, provide further evidence for an association between Rorb and several neurological conditions, and describe an allelic series of Rorb mutant mice that will be useful for dissecting thalamocortical afferent(TCA) development, neural cell fate determination, and as animal models exhibiting transcriptomic shifts in neurological conditions such as epilepsy, bipolar disorder, and ASD.

Spalt modifies EGFR-mediated induction of chordotonal precursors in the embryonic PNS of Drosophila promoting the development of oenocytes

Development ◽  
2001 ◽  
Vol 128 (5) ◽  
pp. 711-722 ◽  
Author(s):  
T.E. Rusten ◽  
R. Cantera ◽  
J. Urban ◽  
G. Technau ◽  
F.C. Kafatos ◽  
...  
Keyword(s):  
Nervous System ◽  
Cell Fate ◽  
System Development ◽  
Cell Types ◽  
Nervous System Development ◽  
Dual Function ◽  
Evolutionarily Conserved ◽  
A Cell ◽  
And Migration

Genes of the spalt family encode nuclear zinc finger proteins. In Drosophila melanogaster, they are necessary for the establishment of head/trunk identity, correct tracheal migration and patterning of the wing imaginal disc. Spalt proteins display a predominant pattern of expression in the nervous system, not only in Drosophila but also in species of fish, mouse, frog and human, suggesting an evolutionarily conserved role for these proteins in nervous system development. Here we show that Spalt works as a cell fate switch between two EGFR-induced cell types, the oenocytes and the precursors of the pentascolopodial organ in the embryonic peripheral nervous system. We show that removal of spalt increases the number of scolopodia, as a result of extra secondary recruitment of precursor cells at the expense of the oenocytes. In addition, the absence of spalt causes defects in the normal migration of the pentascolopodial organ. The dual function of spalt in the development of this organ, recruitment of precursors and migration, is reminiscent of its role in tracheal formation and of the role of a spalt homologue, sem-4, in the Caenorhabditis elegans nervous system.

Postnatal testosterone may be an important mediator of the association between prematurity and male neurodevelopmental disorders: a hypothesis

2017 ◽  
Vol 29 (2) ◽  
Author(s):  
Timothy R. Rice
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurodevelopmental Disorders ◽  
System Development ◽  
Explanatory Power ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Special Focus ◽  
Important Mediator ◽  
Androgen Exposure

Abstract Children born premature are at risk for neurodevelopmental disorders, including autism and schizophrenia. This piece advances the hypothesis that altered androgen exposure observed in premature infants is an important mediator of the neurodevelopmental risk in males associated with prematurity. Specifically, the alterations of normative physiologic postnatal activations of the hypothalamic-pituitary-gonadal axis that occur in preterm males are hypothesized to contribute to the risk of neuropsychiatric pathology of prematurity through altered androgen-mediated organizational effects on the developing brain. The physiology of testosterone and male central nervous system development in full-term births is reviewed and compared to the developmental processes of prematurity. The effects of the altered testosterone physiology observed within prematurity outside of the central nervous system are reviewed as a segue into a discussion of the effects within the nervous system, with a special focus on autism spectrum disorders and attention deficit hyperactivity disorder. The explanatory power of this model is reviewed as a supplement to the preexisting models of prematurity and neurodevelopmental risk, including infection and other perinatal central nervous system insults. The emphasis is placed on altered androgen exposure as serving as just one among many mediators of neurodevelopmental risk that may be of interest for further research and evidence-based investigation. Implications for diagnosis, management and preventative treatments conclude the piece.

scholarly journals Spatiotemporal expression of IgLON family members in the developing mouse nervous system

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sydney Fearnley ◽  
Reesha Raja ◽  
Jean-François Cloutier
Keyword(s):  
Spinal Cord ◽  
Nervous System ◽  
Developmental Disorders ◽  
System Development ◽  
Expression Patterns ◽  
Family Members ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Spatiotemporal Expression ◽  
Developing Nervous System

AbstractDifferential expression of cell adhesion molecules in neuronal populations is one of the many mechanisms promoting the formation of functional neural circuits in the developing nervous system. The IgLON family consists of five cell surface immunoglobulin proteins that have been associated with various developmental disorders, such as autism spectrum disorder, schizophrenia, and major depressive disorder. However, there is still limited and fragmented information about their patterns of expression in certain regions of the developing nervous system and how their expression contributes to their function. Utilizing an in situ hybridization approach, we have analyzed the spatiotemporal expression of all IgLON family members in the developing mouse brain, spinal cord, eye, olfactory epithelium, and vomeronasal organ. At one prenatal (E16) and two postnatal (P0 and P15) ages, we show that each IgLON displays distinct expression patterns in the olfactory system, cerebral cortex, midbrain, cerebellum, spinal cord, and eye, indicating that they likely contribute to the wiring of specific neuronal circuitry. These analyses will inform future functional studies aimed at identifying additional roles for these proteins in nervous system development.

scholarly journals ngn-1/neurogenin Activates Transcription of Multiple Terminal Selector Transcription Factors in the Caenorhabditis elegans Nervous System

2020 ◽  
Vol 10 (6) ◽  
pp. 1949-1962 ◽  
Author(s):  
Elyse L. Christensen ◽  
Alexandra Beasley ◽  
Jessica Radchuk ◽  
Zachery E. Mielko ◽  
Elicia Preston ◽  
...  
Keyword(s):  
Nervous System ◽  
Transcription Factors ◽  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Neural Development ◽  
System Development ◽  
Neuronal Cell ◽  
Nervous System Development ◽  
Link Type ◽  
Neuroblast Migration

Proper nervous system development is required for an organism’s survival and function. Defects in neurogenesis have been linked to neurodevelopmental disorders such as schizophrenia and autism. Understanding the gene regulatory networks that orchestrate neural development, specifically cascades of proneural transcription factors, can better elucidate which genes are most important during early neurogenesis. Neurogenins are a family of deeply conserved factors shown to be both necessary and sufficient for the development of neural subtypes. However, the immediate downstream targets of neurogenin are not well characterized. The objective of this study was to further elucidate the role of ngn-1/neurogenin in nervous system development and to identify its downstream transcriptional targets, using the nematode Caenorhabditis elegans as a model for this work. We found that ngn-1 is required for axon outgrowth, nerve ring architecture, and neuronal cell fate specification. We also showed that ngn-1 may have roles in neuroblast migration and epithelial integrity during embryonic development. Using RNA sequencing and comparative transcriptome analysis, we identified eight transcription factors (hlh-34/NPAS1, unc-42/PROP1, ceh-17/PHOX2A, lim-4/LHX6, fax-1/NR2E3, lin-11/LHX1, tlp-1/ZNF503, and nhr-23/RORB) whose transcription is activated, either directly or indirectly, by ngn-1. Our results show that ngn-1 has a role in transcribing known terminal regulators that establish and maintain cell fate of differentiated neural subtypes and confirms that ngn-1 functions as a proneural transcription factor in C. elegans neurogenesis.

scholarly journals 60 Are gangliogliomas in children and adults disorders of nervous system development?

2018 ◽  
Vol 45 (S3) ◽  
pp. S10-S10
Author(s):  
Qiang Jiang ◽  
Jamie Zagozewski ◽  
Paolo Nozza ◽  
Beverly Wilson ◽  
Frank Van Landeghem ◽  
...  
Keyword(s):  
Nervous System ◽  
Cell Fate ◽  
Validation Cohort ◽  
Ganglion Cells ◽  
Point Mutations ◽  
Nervous System Development ◽  
Braf V600e ◽  
Low Grade ◽  
Braf Mutations ◽  
Neuronal Markers

INTRODUCTION: Gangliogliomas (GGs) are neuroepithelial tumours of the central nervous system (CNS) composed of mature ganglion cells or a mixed population of ganglion and glial cells. Microarray data of low grade gliomas (LGG) including GGs revealed overexpression of the Dlx2 gene, a homeobox gene essential for interneuron migration and differentiation. We hypothesized that GGs are arrested in development, and began to explore the role of the Dlx2 gene. BRAF rearrangements and BRAF V600E point mutations have been reported in pediatric LGG. METHODS: DLX2 expression was examined in GGs using immunofluorescence (IF) and immunohistochemistry (IHC) labelling of formalin fixed paraffin embedded (FFPE) tissue sections, along with staining of glial and neuronal markers. BRAF mutations were detected using a commercial antibody and/or sequence verification of the DNA extracted from the FFPE blocks. RESULTS: In the Discovery cohort 10/30 were DLX2+ (33.3%) and in the Validation cohort 15/40 were DLX2+ (37.5%). Of these 15 cases, 15 were GFAP+ (100%), 15 were synaptophysin and/or NeuN+ (100%), and 13 were OLIG2+ (86.7%); 6 had a BRAF V600E mutation (40.0%). For the Validation cohort of 40 GGs, 28 were OLIG2+ (70.0%); 13/28 co-expressed DLX2 (46.4%). 18/40 cases had a BRAF V600 mutation(17 V600E, 1 V600G; 45.0%) and 6/18 were DLX2+ (33.3%). CONCLUSIONS: DLX2 is expressed in GGs in both neuronal and glial marker expressing tumour cells. Our results support that GGs arise from CNS progenitors arrested at the neuronal-glial cell fate “decision” point.

scholarly journals cnd-1/NeuroD1 Functions with the Homeobox Gene ceh-5/Vax2 and Hox Gene ceh-13/labial To Specify Aspects of RME and DD Neuron Fate in Caenorhabditis elegans

2020 ◽  
Vol 10 (9) ◽  
pp. 3071-3085
Author(s):  
Wendy Aquino-Nunez ◽  
Zachery E Mielko ◽  
Trae Dunn ◽  
Elise M Santorella ◽  
Ciara Hosea ◽  
...  
Keyword(s):  
Nervous System ◽  
Transcription Factor ◽  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Neural Development ◽  
Nervous System Development ◽  
Cell Fate Specification ◽  
Hox Gene ◽  
Fate Specification

Abstract Identifying the mechanisms behind neuronal fate specification are key to understanding normal neural development in addition to neurodevelopmental disorders such as autism and schizophrenia. In vivo cell fate specification is difficult to study in vertebrates. However, the nematode Caenorhabditis elegans, with its invariant cell lineage and simple nervous system of 302 neurons, is an ideal organism to explore the earliest stages of neural development. We used a comparative transcriptome approach to examine the role of cnd-1/NeuroD1 in C. elegans nervous system development and function. This basic helix-loop-helix transcription factor is deeply conserved across phyla and plays a crucial role in cell fate specification in both the vertebrate nervous system and pancreas. We find that cnd-1 controls expression of ceh-5, a Vax2-like homeobox class transcription factor, in the RME head motorneurons and PVQ tail interneurons. We also show that cnd-1 functions redundantly with the Hox gene ceh-13/labial in defining the fate of DD1 and DD2 embryonic ventral nerve cord motorneurons. These data highlight the utility of comparative transcriptomes for identifying transcription factor targets and understanding gene regulatory networks.

scholarly journals Identification and functional analysis of long non-coding RNAs in autism spectrum disorders

2020 ◽  
Author(s):  
Zhan Tong ◽  
Yuan Zhou ◽  
Juan Wang
Keyword(s):  
Nervous System ◽  
Transcriptional Regulation ◽  
Copy Number ◽  
System Development ◽  
Copy Number Variant ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Biological Pathways ◽  
Non Coding Rnas

ABSTRACTBackgroundGenetic and environmental factors, alone or in combination, contribute to the pathogenesis of autism spectrum disorder (ASD). Although many protein-coding genes have now been identified as disease risk genes for ASD, a detailed illustration of long non-coding RNAs (lncRNAs) associated with ASD remains elusive. In this study, our aim was to identify ASD-related lncRNAs and explore their functions and associated biological pathways in autism.MethodsASD-related lncRNAs were identified based on genomic variant data of individuals with ASD from a twin study, and further validated using an independent copy number variant (CNV) dataset. The functions and associated biological pathways of ASD-related lncRNAs were explored by enrichment analysis of three different types of functional neighbor genes (i.e. genomic neighbors, competing endogenous RNA (ceRNA) neighbors and gene co-expression neighbors in the cortex). The differential functions of ASD-related lncRNAs in distinct brain regions were demonstrated by using gene co-expression network analysis based on tissue-specific gene expression profiles. Moreover, a functional network analysis were conducted for highly reliable functional neighbor genes of ASD-related lncRNAs. Finally, several potential drugs were predicted based on the enrichment of drug-induced pathway sets in ASD-altered biological pathway list.ResultsIn total, 532 ASD-related lncRNAs were identified, and 86.7% of these ASD-related lncRNAs were further validated by a copy number variant (CNV) dataset. Most of functional neighbor genes of ASD-related lncRNAs were enriched in several functions and biological pathways, including nervous system development, inflammatory response and transcriptional regulation. As a set, ASD-related lncRNAs were mainly associated with nervous system development and dopaminergic synapse in the cortex, but associated with transcriptional regulation in the cerebellum. Moreover, all highly reliable functional neighbor genes were connected in a single functional network. Finally, several potential drugs were predicted and partly supported by the previous reports.ConclusionsWe concluded that ASD-related lncRNAs participate in the pathogenesis of ASD through various known biological pathways, which may be differential in distinct brain regions. And detailed investigation of ASD-related lncRNAs also provided clues for developing potential ASD diagnosis biomarker and therapy.

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