18 research outputs found
Towards a genome-wide transcriptogram: the Saccharomyces cerevisiae case
A genome modular classification that associates cellular processes to modules could lead to a method to quantify the differences in gene expression levels in different cellular stages or conditions: the transcriptogram, a powerful tool for assessing cell performance, would be at hand. Here we present a computational method to order genes on a line that clusters strongly interacting genes, defining functional modules associated with gene ontology terms. The starting point is a list of genes and a matrix specifying their interactions, available at large gene interaction databases. Considering the Saccharomyces cerevisiae genome we produced a succession of plots of gene transcription levels for a fermentation process. These plots discriminate the fermentation stage the cell is going through and may be regarded as the first versions of a transcriptogram. This method is useful for extracting information from cell stimuli/responses experiments, and may be applied with diagnostic purposes to different organisms
Postnatal expression profiles of atypical cadherin FAT1 suggest its role in autism
Genetic studies have linked FAT1 (FAT atypical cadherin 1) with autism spectrum disorder (ASD); however, the role that FAT1 plays in ASD remains unknown. In mice, the function of Fat1 has been primarily implicated in embryonic nervous system development with less known about its role in postnatal development. We show for the first time that FAT1 protein is expressed in mouse postnatal brains and is enriched in the cerebellum, where it localizes to granule neurons and Golgi cells in the granule layer, as well as inhibitory neurons in the molecular layer. Furthermore, subcellular characterization revealed FAT1 localization in neurites and soma of granule neurons, as well as being present in the synaptic plasma membrane and postsynaptic densities. Interestingly, FAT1 expression was decreased in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) from individuals with ASD. These findings suggest a novel role for FAT1 in postnatal development and may be particularly important for cerebellum function. As the cerebellum is one of the vulnerable brain regions in ASD, our study warrants further investigation of FAT1 in the disease etiology
Autism Spectrum Disorders and Neuropathology of the Cerebellum
The cerebellum contains the largest number of neurons and synapses of any structure in the central nervous system. The concept that the cerebellum is solely involved in fine motor function has become outdated; substantial evidence has accumulated linking the cerebellum with higher cognitive functions including language. Cerebellar deficits have been implicated in autism for more than two decades. The computational power of the cerebellum is essential for many, if not most of the processes that are perturbed in autism including language and communication, social interactions, stereotyped behavior, motor activity and motor coordination, and higher cognitive functions. The link between autism and cerebellar dysfunction should not be surprising to those who study its cellular, physiological, and functional properties. Postmortem studies have revealed neuropathological abnormalities in cerebellar cellular architecture while studies on mouse lines with cell loss or mutations in single genes restricted to cerebellar Purkinje cells have also strongly implicated this brain structure in contributing to the autistic phenotype. This connection has been further substantiated by studies investigating brain damage in humans restricted to the cerebellum. In this review, we summarize advances in research on idiopathic autism and three genetic forms of autism that highlight the key roles that the cerebellum plays in this spectrum of neurodevelopmental disorders
A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons
Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals’ ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into 1) cytoskeletal regulators, e.g. motors and small RhoGTPase regulators; 2) adhesion molecules, e.g. cadherins, NCAM, and neurexin superfamily; 3) cell surface receptors, e.g. glutamatergic receptors and receptor tyrosine kinases; 4) signaling molecules, e.g. protein kinases and phosphatases; and 5) synaptic proteins, e.g. vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families
Transcriptomic analysis of isolated and pooled human postmortem cerebellar Purkinje cells in autism spectrum disorders
At present, the neuronal mechanisms underlying the diagnosis of autism spectrum disorder (ASD) have not been established. However, studies from human postmortem ASD brains have consistently revealed disruptions in cerebellar circuitry, specifically reductions in Purkinje cell (PC) number and size. Alterations in cerebellar circuitry would have important implications for information processing within the cerebellum and affect a wide range of human motor and non-motor behaviors. Laser capture microdissection was performed to obtain pure PC populations from a cohort of postmortem control and ASD cases and transcriptional profiles were compared. The 427 differentially expressed genes were enriched for gene ontology biological processes related to developmental organization/connectivity, extracellular matrix organization, calcium ion response, immune function and PC signaling alterations. Given the complexity of PCs and their far-ranging roles in response to sensory stimuli and motor function regulation, understanding transcriptional differences in this subset of cerebellar cells in ASD may inform on convergent pathways that impact neuronal function
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Postnatal expression profiles of atypical cadherin FAT1 suggest its role in autism
Genetic studies have linked
FAT1
(FAT atypical cadherin 1) with autism spectrum disorder (ASD); however, the role that
FAT1
plays in ASD remains unknown. In mice, the function of
Fat1
has been primarily implicated in embryonic nervous system development with less known about its role in postnatal development. We show for the first time that FAT1 protein is expressed in mouse postnatal brains and is enriched in the cerebellum, where it localizes to granule neurons and Golgi cells in the granule layer, as well as inhibitory neurons in the molecular layer. Furthermore, subcellular characterization revealed FAT1 localization in neurites and soma of granule neurons, as well as being present in the synaptic plasma membrane and postsynaptic densities. Interestingly, FAT1 expression was decreased in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) from individuals with ASD. These findings suggest a novel role for FAT1 in postnatal development and may be particularly important for cerebellum function. As the cerebellum is one of the vulnerable brain regions in ASD, our study warrants further investigation of FAT1 in the disease etiology.
Summary:
This study describes a novel role of FAT1 in postnatal brain development and its potential contribution to the etiology of autism spectrum disorder
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Altered Expression of Cadherin-8 and Cadherin-11 in Neural Circuit Development: Implications for Autism
Abstract Autism spectrum disorder (ASD) is a neurological condition characterized by difficulties in social interaction, communication, and behavior. The classical type II cadherins cadherin-8 (Cdh8, CDH8) and cadherin-11 (Cdh11, CDH11) have been implicated as autism risk gene candidates. To explore the role of cadherins in the etiology of autism, we investigated their expression patterns during mouse brain development and analyzed their functions using Cdh11 knockout mice. Expression of cadherin-8 and cadherin-11 was developmentally regulated and enriched in cortex, hippocampus, and thalamus/striatum during the peak of dendrite formation and synaptogenesis. Cadherin-8 preferentially localized to excitatory synapses where it interacted with neuroligin-1. Levels of cadherin-8, neuroligin-1, and PSD-95 were all significantly increased in Cdh11 knockout brains. Additionally, Cdh11 -/- hippocampal neurons exhibited increased dendritic complexity along with altered neuronal and synaptic activity. Similar to the expression profiles in Cdh11 knockout mice, induced pluripotent stem cell (iPSC)-derived cortical neural precursor cells (NPCs) and cortical organoids generated from individuals with autism showed elevated CDH8 expression levels while CDH11 expression levels were decreased. Together, these results strongly suggest that cadherin-8 and cadherin-11 are involved in regulating the development of neuronal circuitry and that alterations in the expression levels of cadherin-8 and cadherin-11 may contribute to the etiology of autism
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