scholarly journals Regulation of Prefrontal Patterning, Connectivity and Synaptogenesis by Retinoic Acid

2019 ◽  
Author(s):  
Mikihito Shibata ◽  
Kartik Pattabiraman ◽  
Belen Lorente-Galdos ◽  
David Andrijevic ◽  
Xiaojun Xing ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Critical Role ◽  
Autism Spectrum ◽  
Lateral Expansion ◽  
Gene Encoding ◽  
Reciprocal Connections ◽  
Layer 4 ◽  
Human Frontal Cortex ◽  
Anthropoid Primates ◽  
And Function

AbstractThe prefrontal cortex (PFC) and its reciprocal connections with the mediodorsal thalamus (MD) are crucial for cognitive flexibility and working memory1–4 and are thought to be altered in several disorders such as autism spectrum disorder5, 6 and schizophrenia6–9. While developmental mechanisms governing regional patterning of the rodent cerebral cortex have been characterized10–15, the mechanisms underlying the development of PFC-MD connectivity and the lateral expansion of PFC with distinct granular layer 4 in anthropoid primates16–23 have not been elucidated. Here we report increased concentration of retinoic acid (RA), a signaling molecule involved in brain development and function24, 25 in the prospective PFC areas of human and macaque, compared to mouse, during mid-fetal development, a crucial period for cortical circuit assembly. In addition, we observed the lateral expansion of RA synthesizing enzyme, ALDH1A3, expression in mid-fetal macaque and human frontal cortex, compared to mouse. Furthermore, we found that enrichment of RA signaling is restricted to the prospective PFC by CYP26B1, a gene encoding an RA-catabolizing enzyme upregulated in the mid-fetal motor cortex. Gene deletion in mice revealed that RA signaling through anteriorly upregulated RA receptors, Rxrg and Rarb, and Cyp26b1-dependent catabolism is required for the proper molecular patterning of PFC and motor areas, the expression of the layer 4 marker RORB, intra-PFC synaptogenesis, and the development of reciprocal PFC-MD connectivity. Together, these findings reveal a critical role for RA signaling in PFC development and, potentially, its evolutionary expansion.

scholarly journals Neuroligin-3: A Circuit-Specific Synapse Organizer That Shapes Normal Function and Autism Spectrum Disorder-Associated Dysfunction

2021 ◽  
Vol 14 ◽  
Author(s):  
Motokazu Uchigashima ◽  
Amy Cheung ◽  
Kensuke Futai
Keyword(s):  
Autism Spectrum Disorder ◽  
Molecular Mechanism ◽  
Strong Association ◽  
Critical Role ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Synaptic Signaling ◽  
Syndromic Asd ◽  
Chemical Synapses ◽  
And Function

Chemical synapses provide a vital foundation for neuron-neuron communication and overall brain function. By tethering closely apposed molecular machinery for presynaptic neurotransmitter release and postsynaptic signal transduction, circuit- and context- specific synaptic properties can drive neuronal computations for animal behavior. Trans-synaptic signaling via synaptic cell adhesion molecules (CAMs) serves as a promising mechanism to generate the molecular diversity of chemical synapses. Neuroligins (Nlgns) were discovered as postsynaptic CAMs that can bind to presynaptic CAMs like Neurexins (Nrxns) at the synaptic cleft. Among the four (Nlgn1-4) or five (Nlgn1-3, Nlgn4X, and Nlgn4Y) isoforms in rodents or humans, respectively, Nlgn3 has a heterogeneous expression and function at particular subsets of chemical synapses and strong association with non-syndromic autism spectrum disorder (ASD). Several lines of evidence have suggested that the unique expression and function of Nlgn3 protein underlie circuit-specific dysfunction characteristic of non-syndromic ASD caused by the disruption of Nlgn3 gene. Furthermore, recent studies have uncovered the molecular mechanism underlying input cell-dependent expression of Nlgn3 protein at hippocampal inhibitory synapses, in which trans-synaptic signaling of specific alternatively spliced isoforms of Nlgn3 and Nrxn plays a critical role. In this review article, we overview the molecular, anatomical, and physiological knowledge about Nlgn3, focusing on the circuit-specific function of mammalian Nlgn3 and its underlying molecular mechanism. This will provide not only new insight into specific Nlgn3-mediated trans-synaptic interactions as molecular codes for synapse specification but also a better understanding of the pathophysiological basis for non-syndromic ASD associated with functional impairment in Nlgn3 gene.

scholarly journals Cell signaling directing the formation and function of hemogenic endothelium during murine embryogenesis

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3194-3204 ◽  
Author(s):  
Lauren C. Goldie ◽  
Jennifer L. Lucitti ◽  
Mary E. Dickinson ◽  
Karen K. Hirschi
Keyword(s):  
Endothelial Cells ◽  
Retinoic Acid ◽  
Cell Signaling ◽  
Vascular Endothelium ◽  
Critical Role ◽  
Hemogenic Endothelium ◽  
Hematopoietic Progenitors ◽  
And Function ◽  
Molecular Signals ◽  
Definitive Hematopoiesis

Abstract During developmental hematopoiesis, multilineage hematopoietic progenitors are thought to derive from a subset of vascular endothelium. Herein, we define the phenotype of such hemogenic endothelial cells and demonstrate, on a clonal level, that they exhibit multilineage hematopoietic potential. Furthermore, we have begun to define the molecular signals that regulate their development. We found that the formation of yolk sac hemogenic endothelium and its hematopoietic potential were significantly impaired in the absence of retinoic acid (RA) signaling, and could be restored in RA-deficient (Raldh2−/−) embryos by provision of exogenous RA in utero. Thus, we identify a novel, critical role for RA signaling in the development of hemogenic endothelium that contributes to definitive hematopoiesis.

scholarly journals Global kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Corvin Walter ◽  
Adinarayana Marada ◽  
Tamara Suhm ◽  
Ralf Ernsberger ◽  
Vera Muders ◽  
...  
Keyword(s):  
Critical Role ◽  
Transcriptional Response ◽  
Autism Spectrum ◽  
Mitochondrial Proteome ◽  
Mitochondrial Structure ◽  
Disease Mechanisms ◽  
Precursor Proteins ◽  
And Function ◽  
Import Receptor ◽  
The Ideal

AbstractThe translocase of the outer mitochondrial membrane TOM constitutes the organellar entry gate for nearly all precursor proteins synthesized on cytosolic ribosomes. Thus, TOM presents the ideal target to adjust the mitochondrial proteome upon changing cellular demands. Here, we identify that the import receptor TOM70 is targeted by the kinase DYRK1A and that this modification plays a critical role in the activation of the carrier import pathway. Phosphorylation of TOM70Ser91 by DYRK1A stimulates interaction of TOM70 with the core TOM translocase. This enables transfer of receptor-bound precursors to the translocation pore and initiates their import. Consequently, loss of TOM70Ser91 phosphorylation results in a strong decrease in import capacity of metabolite carriers. Inhibition of DYRK1A impairs mitochondrial structure and function and elicits a protective transcriptional response to maintain a functional import machinery. The DYRK1A-TOM70 axis will enable insights into disease mechanisms caused by dysfunctional DYRK1A, including autism spectrum disorder, microcephaly and Down syndrome.

scholarly journals Tsc1-mTOR signaling controls the structure and function of midbrain dopamine neurons

2018 ◽  
Author(s):  
Polina Kosillo ◽  
Natalie M. Doig ◽  
Alexander H.C.W. Agopyan-Miu ◽  
Kamran Ahmed ◽  
Lisa Conyers ◽  
...  
Keyword(s):  
Critical Role ◽  
Dopamine Neurons ◽  
Negative Regulator ◽  
Gene Encoding ◽  
Cognitive Behaviors ◽  
High Prevalence ◽  
Midbrain Dopamine ◽  
And Function ◽  
Mtor Complex 1 ◽  
Midbrain Dopamine Neurons

SummarymTOR complex 1 (mTORC1) is a central coordinator of cell growth and metabolism. Mutations in regulators of mTORC1 cause syndromic disorders with a high prevalence of cognitive and psychiatric conditions. To elucidate the cellular origins of these manifestations, we conditionally deleted the gene encoding the mTORC1 negative regulator Tsc1 from mouse midbrain dopamine neurons, which modulate motor, affective, and cognitive behaviors that are frequently affected in psychiatric disorders. Loss of Tsc1 and constitutive activation of mTORC1 strongly impacted the properties of dopamine neurons, causing somatodendritic hypertrophy, reduced intrinsic excitability, altered axon terminal ultrastructure, and severely impaired dopamine release. These perturbations were associated with selective deficits in cognitive flexibility, which could be prevented by genetic reduction of the obligatory mTORC1 protein Raptor. Our results establish a critical role for mTORC1 in setting the functional properties of midbrain dopamine neurons, and indicate that dopaminergic dysfunction may underlie cognitive inflexibility in mTOR-related syndromes.

scholarly journals Autism-like behavior caused by deletion of vaccinia-related kinase 3 is improved by TrkB stimulation

2017 ◽  
Vol 214 (10) ◽  
pp. 2947-2966 ◽  
Author(s):  
Myung-Su Kang ◽  
Tae-Yong Choi ◽  
Hye Guk Ryu ◽  
Dohyun Lee ◽  
Seung-Hyun Lee ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Neuronal Development ◽  
Critical Role ◽  
Autism Spectrum ◽  
Synaptic Structure ◽  
Stereotyped Behaviors ◽  
Development And Differentiation ◽  
And Function ◽  
Tyrosine Receptor Kinase ◽  
Deficient Mice

Vaccinia-related kinases (VRKs) are multifaceted serine/threonine kinases that play essential roles in various aspects of cell signaling, cell cycle progression, apoptosis, and neuronal development and differentiation. However, the neuronal function of VRK3 is still unknown despite its etiological potential in human autism spectrum disorder (ASD). Here, we report that VRK3-deficient mice exhibit typical symptoms of autism-like behavior, including hyperactivity, stereotyped behaviors, reduced social interaction, and impaired context-dependent spatial memory. A significant decrease in dendritic spine number and arborization were identified in the hippocampus CA1 of VRK3-deficient mice. These mice also exhibited a reduced rectification of AMPA receptor–mediated current and changes in expression of synaptic and signaling proteins, including tyrosine receptor kinase B (TrkB), Arc, and CaMKIIα. Notably, TrkB stimulation with 7,8-dihydroxyflavone reversed the altered synaptic structure and function and successfully restored autism-like behavior in VRK3-deficient mice. These results reveal that VRK3 plays a critical role in neurodevelopmental disorders and suggest a potential therapeutic strategy for ASD.

Development of Neural Structure and Function in Autism Spectrum Disorder: Potential Implications for Learning Language

2020 ◽  
Vol 29 (4) ◽  
pp. 1783-1797
Author(s):  
Kelly L. Coburn ◽  
Diane L. Williams
Keyword(s):  
Autism Spectrum Disorder ◽  
Language Development ◽  
Diffusion Tensor ◽  
Autism Spectrum ◽  
Language Intervention ◽  
Spectrum Disorder ◽  
Autistic Children ◽  
Neural Structure ◽  
Complex Information ◽  
And Function

Purpose Neurodevelopmental processes that begin during gestation and continue throughout childhood typically support language development. Understanding these processes can help us to understand the disruptions to language that occur in neurodevelopmental conditions, such as autism spectrum disorder (ASD). Method For this tutorial, we conducted a focused literature review on typical postnatal brain development and structural and functional magnetic resonance imaging, diffusion tensor imaging, magnetoencephalography, and electroencephalography studies of the neurodevelopmental differences that occur in ASD. We then integrated this knowledge with the literature on evidence-based speech-language intervention practices for autistic children. Results In ASD, structural differences include altered patterns of cortical growth and myelination. Functional differences occur at all brain levels, from lateralization of cortical functions to the rhythmic activations of single neurons. Neuronal oscillations, in particular, could help explain disrupted language development by elucidating the timing differences that contribute to altered functional connectivity, complex information processing, and speech parsing. Findings related to implicit statistical learning, explicit task learning, multisensory integration, and reinforcement in ASD are also discussed. Conclusions Consideration of the neural differences in autistic children provides additional scientific support for current recommended language intervention practices. Recommendations consistent with these neurological findings include the use of short, simple utterances; repetition of syntactic structures using varied vocabulary; pause time; visual supports; and individualized sensory modifications.

The Role of the SLP in Autism Spectrum Disorder Screening and Assessment

2008 ◽  
Vol 15 (2) ◽  
pp. 50-59 ◽  
Author(s):  
Amy Philofsky
Keyword(s):  
Language Development ◽  
Critical Role ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Children With Asd ◽  
Prevalence Estimates ◽  
Notable Increase ◽  
Screening Assessment ◽  
Critical Components

AbstractRecent prevalence estimates for autism have been alarming as a function of the notable increase. Speech-language pathologists play a critical role in screening, assessment and intervention for children with autism. This article reviews signs that may be indicative of autism at different stages of language development, and discusses the importance of several psychometric properties—sensitivity and specificity—in utilizing screening measures for children with autism. Critical components of assessment for children with autism are reviewed. This article concludes with examples of intervention targets for children with ASD at various levels of language development.

The Laryngeal Epithelium in Reflux

2011 ◽  
Vol 21 (3) ◽  
pp. 112-117 ◽  
Author(s):  
Elizabeth Erickson-Levendoski ◽  
Mahalakshmi Sivasankar
Keyword(s):  
Laryngopharyngeal Reflux ◽  
Critical Role ◽  
Structure And Function ◽  
Laryngeal Disease ◽  
Health And Disease ◽  
And Function ◽  
The Impact

The epithelium plays a critical role in the maintenance of laryngeal health. This is evident in that laryngeal disease may result when the integrity of the epithelium is compromised by insults such as laryngopharyngeal reflux. In this article, we will review the structure and function of the laryngeal epithelium and summarize the impact of laryngopharyngeal reflux on the epithelium. Research investigating the ramifications of reflux on the epithelium has improved our understanding of laryngeal disease associated with laryngopharyngeal reflux. It further highlights the need for continued research on the laryngeal epithelium in health and disease.

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