A Novel Hap1–Tsc1 Interaction Regulates Neuronal mTORC1 Signaling and Morphogenesis in the Brain

Mejia, Luis A.; Litterman, Nadia K.; Ikeuchi, Yoshiho; Torre-Ubieta, Luis de la; Bennett, Eric J.; Zhang, Chi; Bonni, Azad

doi:10.1523/jneurosci.2290-13.2013

Cited by 18 publications

(27 citation statements)

References 28 publications

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“…Correspondingly, the Target Filter results suggested that PI3K/AKT/mTOR signaling may be altered via aberrant miRNA regulation of the tumor suppressor protein Tsc1 (table 5). The upregulation of miR-721 and subsequent downregulation of Tsc1 is significant with relevance to FASD-related abnormalities, given current evidence that knockdown of Tsc1 or its functional partner, huntingtin-associated protein 1 (Hap1) , profoundly impairs the positioning of pyramidal neurons in the hippocampus [79], leading to long-term neurological impairment including cognitive deficits and learning impairments [80]. These results argue that altered epigenetic mechanisms, including histone modifications and miRNA regulatory control, may reflect consequences of neurodevelopmental ethanol exposure that do not have a specific relationship to stress response but nonetheless exert long-term functional changes within the adult brain.…”

Section: Discussionmentioning

confidence: 99%

Third Trimester-Equivalent Ethanol Exposure Is Characterized by an Acute Cellular Stress Response and an Ontogenetic Disruption of Genes Critical for Synaptic Establishment and Function in Mice

Kleiber

Laufer²,

Stringer³

et al. 2014

Dev Neurosci

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The developing brain is remarkably sensitive to alcohol exposure, resulting in the wide range of cognitive and neurobehavioral characteristics categorized under the term fetal alcohol spectrum disorders (FASD). The brain is particularly susceptible to alcohol during synaptogenesis, a process that occurs heavily during the third trimester and is characterized by the establishment and pruning of neural circuitry; however, the molecular response of the brain to ethanol during synaptogenesis has not been documented. To model a binge-like exposure during the third-trimester neurodevelopmental equivalent, neonate mice were given a high (5 g/kg over 2 h) dose of ethanol at postnatal day 7. Acute transcript changes within the brain were assessed using expression arrays and analyzed for associations with gene ontology functional categories, canonical pathways, and gene network interactions. The short-term effect of ethanol was characterized by an acute stress response and a downregulation of energetically costly cellular processes. Further, alterations to a number of genes with roles in synaptic transmission and hormonal signaling, particularly those associated with the neuroendocrine development and function, were evident. Ethanol exposure during synaptogenesis was also associated with altered histone deacetylase and microRNA transcript levels, suggesting that abnormal epigenetic patterning may maintain some of the persistent molecular consequences of developmental ethanol exposure. The results shed insight into the sensitivity of the brain to ethanol during the third-trimester equivalent and outline how ethanol-induced alterations to genes associated with neural connectivity may contribute to FASD phenotypes.

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Section: Discussionmentioning

confidence: 99%

Third Trimester-Equivalent Ethanol Exposure Is Characterized by an Acute Cellular Stress Response and an Ontogenetic Disruption of Genes Critical for Synaptic Establishment and Function in Mice

Kleiber

Laufer²,

Stringer³

et al. 2014

Dev Neurosci

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“…To assess precise positions of ribosome occupancy on mRNAs, uniquely aligning reads with length between 25 and 35 nt were used. The unique reads were mapped to CDS coordinates using mapToTranscripts function from GenomicFeatures R package (Lawrence et al, 2013). The reads were assigned to the positions corresponding to the first nucleotide of the P-site, by shifting the 5Ј end of each read by ϩ12 (for reads 25-30 nt long), ϩ13 (31-34 nt) or ϩ14 (35 nt) positions.…”

Section: Methodsmentioning

confidence: 99%

“…CTSSs with at least four pyrimidines in the 5Јend 5 nt were identified as producing 5ЈTOP-like motif-containing mRNAs. For each dataset, total CTSS and 5ЈTOP-preceding CTSS were mapped within 500 bp to both directions of transcription start sites of canonical transcripts using GenomicAlignments' summarizeOverlaps function (Lawrence et al, 2013). The 5ЈTOP ratio was calculated as the division of 5ЈTOPpreceding CTSS count and total CTSS count for each gene and each dataset.…”

Section: Methodsmentioning

confidence: 99%

“…Pairs of oligonucleotides 5Ј-GGTTTAAAGATGGGAAGCAGT CAAGTTAACTCTGCTTCCCATCTTTAAACCCTTTTTG-3Ј and 5Ј-AATTCAAAAAGGGTTTAAAGATGGGAAGCAGAGTTAACTTGACT GCTTCCCATCTTTAAACC-3Ј, 5Ј-GAAAGAGCCCAGAAGAGCTTG CAAGTTAACGAAGCTCTTCTGGGCTCTTTCCTTTTTG-3Ј and 5Ј-AATTCAAAAAGGAAAGAGCCCAGAAGAGCTTCGTTAACTTGCAA GCTCTTCTGGGCTCTTTC-3Ј were cloned into U6 RNAi plasmid to generate palladin RNAi 1 and 2, respectively, as described previously (Gaudilliere et al, 2002). The TSC1 RNAi plasmid has been described previously (Mejia et al, 2013).…”

Section: Methodsmentioning

confidence: 99%

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Palladin Is a Neuron-Specific Translational Target of mTOR Signaling That Regulates Axon Morphogenesis

et al. 2018

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The mTOR signaling pathway regulates protein synthesis and diverse aspects of neuronal morphology that are important for brain development and function. To identify proteins controlled translationally by mTOR signaling, we performed ribosome profiling analyses in mouse cortical neurons and embryonic stem cells upon acute mTOR inhibition. Among proteins whose translation was significantly affected by mTOR inhibition selectively in neurons, we identified the cytoskeletal regulator protein palladin, which is localized within the cell body and axons in hippocampal neurons. Knockdown of palladin eliminated supernumerary axons induced by suppression of the tuberous sclerosis complex protein TSC1 in neurons, demonstrating that palladin regulates neuronal morphogenesis downstream of mTOR signaling. Our findings provide novel insights into an mTOR-dependent mechanism that controls neuronal morphogenesis through translational regulation. This study reports the discovery of neuron-specific protein translational responses to alterations of mTOR activity. By using ribosome profiling analysis, which can reveal the location and quantity of translating ribosomes on mRNAs, multiple aspects of protein translation were quantitatively analyzed in mouse embryonic stem cells and cortical neurons upon acute mTOR inhibition. Neurons displayed distinct patterns of ribosome occupancy for each codon and ribosome stalling during translation at specific positions of mRNAs. Importantly, the cytoskeletal regulator palladin was identified as a translational target protein of mTOR signaling in neurons. Palladin operates downstream of mTOR to modulate axon morphogenesis. This study identifies a novel mechanism of neuronal morphogenesis regulated by mTOR signaling through control of translation of the key protein palladin.

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“…Thanks to collaboration with neuroscientists [20], we are working on Tuberous Sclerosis disease. When neuroscientists model Tuberous Sclerosis in 'in vitro' neuron culture, they observe bigger neuron soma than the control cells.…”

Section: Neurological Disease Applicationsmentioning

confidence: 99%

Digital implementation of Hodgkin–Huxley neuron model for neurological diseases studies

Levi

Khoyratee

Saïghi

et al. 2017

Artif Life Robotics

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Neurological disorders affect millions of people which influence their cognitive and/or motor capabilities. The realization of a prosthesis must consider the biological activity of the cells and the connection between machine and biological cells. Biomimetic neural network is one solution in front of neurological diseases. The neuron replacement should be processed by reproducing the timing and the shape of the spike. Several mathematical equations which model neural activities exist. The most biologically plausible one is the Hodgkin-Huxley (HH) model. The connection between electrical devices and living cells require a tunable real-time system. The FPGA (Field Programmable Gate Array) is a nice component including flexibility, speed and stability. Here we propose an implementation of HH neurons in FPGA serving as a presage for a modulating network opening a large scale of possibilities like damage cells replacement and the study of the effect of the cells disease on the neural network.

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A Novel Hap1–Tsc1 Interaction Regulates Neuronal mTORC1 Signaling and Morphogenesis in the Brain

Cited by 18 publications

References 28 publications

Third Trimester-Equivalent Ethanol Exposure Is Characterized by an Acute Cellular Stress Response and an Ontogenetic Disruption of Genes Critical for Synaptic Establishment and Function in Mice

Third Trimester-Equivalent Ethanol Exposure Is Characterized by an Acute Cellular Stress Response and an Ontogenetic Disruption of Genes Critical for Synaptic Establishment and Function in Mice

Palladin Is a Neuron-Specific Translational Target of mTOR Signaling That Regulates Axon Morphogenesis

Digital implementation of Hodgkin–Huxley neuron model for neurological diseases studies

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