Abstract
Hyperactivated mTOR signaling in the developing brain has been implicated in multiple forms of pathology including tuberous sclerosis complex (TSC). To date, various phenotypic defects such as cortical lamination irregularity, subependymal nodule formation, dysmorphic astrocyte differentiation and dendritic malformation have been described for patients and animal models. However, downstream networks affected in the developing brain by hyperactivated mTOR signaling have yet to be characterized. Here, we present an integrated analysis of transcriptomes and proteomes generated from wild-type and Tsc1/Emx1-Cre forebrains. This led to comprehensive lists of genes and proteins whose expression levels were altered by hyperactivated mTOR signaling. Further incorporation of TSC patient data followed by functional enrichment and network analyses pointed to changes in molecular components and cellular processes associated with neuronal differentiation and morphogenesis as the key downstream events underlying developmental and morphological defects in TSC. Our results provide novel and fundamental molecular bases for understanding hyperactivated mTOR signaling-induced brain defects which can in turn facilitate identification of potential diagnostic markers and therapeutic targets for mTOR signaling-related neurological disorders.
Highlights
Mechanistic target of rapamycin signaling is involved in a broad spectrum of brain development processes including proliferation of neural stem cells, differentiation of neurons, and assembly and maintenance of neuronal circuits1. mTOR signaling functions in regulation of essential neurophysiological behaviors, such as sleep, feeding, and circadian rhythm[1]
Our integrative analysis of transcriptomic and proteomic data incorporates 1) comprehensive transcriptome and proteome profiling of telencephalon tissues using mRNA-sequencing and label-free LC-MS/MS, respectively; (2) identification of differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) by hyperactivated mTOR signaling and their associated cellular processes; (3) identification of tuberous sclerosis complex (TSC)-implicated cellular processes commonly represented by DEGs, DEPs, and DEGs identified from transcriptome profiles of TSC patients; (4) assignation of molecular signatures representing the cellular pathways related to actin cytoskeleton regulation based on the network model; and (5) validation of alterations of the selected molecular signatures in independent TSC1 samples using qRT-PCR and immunohistochemistry analyses
We propose a network model illustrating the linkage between hyperactivated mTOR signaling caused by TSC1 deletion and morphological and developmental defects in the telencephalon
Summary
Mechanistic target of rapamycin (mTOR) signaling is involved in a broad spectrum of brain development processes including proliferation of neural stem cells, differentiation of neurons, and assembly and maintenance of neuronal circuits1. mTOR signaling functions in regulation of essential neurophysiological behaviors, such as sleep, feeding, and circadian rhythm[1]. Choi et al.[7] reported that depletion of TSC1 or TSC2 induced formation of extra axons Together, these data indicate that mTOR signaling is critically involved in neuronal maturation process including cell body growth, axonogenesis, and synaptogenesis. Nie et al.[8] performed gene expression profiling of hippocampal neurons after knockdown of TSC2 and found that expression of Atf[3], a transcription factor (TF), and of Gelsolin (GSN), one of its target genes with a role in regulating actin cytoskeleton, is up-regulated They showed that shRNA-mediated down-regulation of Atf[3] reduces Gelsolin expression and rescues dendritic spine defects, thereby providing a set of downstream effectors of mTOR signaling in developing neurons. This study establishes fundamental molecular bases for phenotypic aberrations caused by hyperactivated mTOR signaling in the brain, which can be useful for isolation of biomarkers and/or therapeutic targets of mTOR signaling-related neurological disorders
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