Shifts in Ribosome Engagement Impact Key Gene Sets in Neurodevelopment and Rett Syndrome Neurons
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ABSTRACT: Translation of many transcripts is highly regulated in the developing brain, and disturbance of translational regulation machinery contributes to neurodevelopmental disorders. In neural progenitor cells, for example, several critical pro-differentiation genes are transcribed, but their translation is repressed to allow rapid translation when appropriate signals to differentiate are received. This layer of translational regulation makes it challenging to directly correlate RNA and protein levels in stem cells and neurons. During early neural development, translation is regulated by several pathways that can impact neuron fate and function. The mTOR-mediated signaling pathway plays a crucial role in the induction of neuron differentiation, axon and dendrite development, and gliogenesis, while being key in the maintenance of pluripotent and neural stem cells {Wang:2013hg}{Agrawal:2014ek}{Ka:2014fq}. Dysregulation of the translation repressor eIF4E-binding protein 2 (4EBP2), a downstream target of mTORC1, leads to an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviors {Gkogkas:2013fh}. The Fragile X Mental Retardation Protein (FMRP), which is encoded by the FMR1 gene {Verkerk:1991hu}, is an RNA binding protein (RBP) that regulates translation through multiple mechanisms {Richter:2015ii}. Loss of expression of FMR1 causes Fragile X Syndrome (FXS), the most common inherited intellectual disability as well as the most prevalent single-gene cause of autism spectrum disorder (ASD). FMRP typically functions as a translational repressor {Li:2001ds} and some studies suggest that FXS results from an inability of neurons to achieve regulated local translation, particularly in response to stimuli {Richter:2015ii}. This suggests important roles for control of translation in stem cells and neurons, and an association with significant risk for neurodevelopmental disorders.
INSTRUMENT(S): Q Exactive
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Pluripotent Stem Cell, Cell Culture, Neuron Of Cerebral Cortex
DISEASE(S): Rett Syndrome
SUBMITTER: 
Ugljesa Djuric
LAB HEAD: Phedias Diamandis
PROVIDER: PXD011961 | Pride | 2020-05-07
REPOSITORIES: Pride
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