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Temporal proteomic profiling of postnatal human cortical development

By Michael S. Breen, Sureyya Ozcan, Jordan M. Ramsey, Zichen Wang, Avi Ma'ayan, Nitin Rustogi, Michael G. Gottschalk, Maree J. Webster, Cynthia Shannon Weickert, Joseph D. Buxbaum, Sabine Bahn

Posted 13 Sep 2017
bioRxiv DOI: 10.1101/188565 (published DOI: 10.1038/s41398-018-0306-4)

Healthy cortical development depends on precise regulation of transcription and translation. However, the relationships between levels of mRNAs and their respective translated proteins have not yet been examined comprehensively in the developing human brain. We surveyed the proteomic landscape of 69 dorsolateral prefrontal cortex samples across seven stages of postnatal life and integrated these data with paired transcriptome data. We detected 911 proteins by liquid chromatography mass-spectrometry, and 83 were significantly associated with postnatal age (FDR P<0.05). Network analysis revealed five modules of co-regulated proteins, three of which correlated with age, including two modules with increasing expression implicated in gliogenesis and NADH-metabolism and one neurogenesis-related module with decreasing expression throughout development. These age-related protein modules overlapped with RNA modules and displayed collinear developmental trajectories between paired RNA and protein expression. We also found that the correspondence between mRNAs and proteins decrease as a function of age, especially for genes involved in neurogenesis and cytoskeleton organization. Finally, intellectual disability and developmental delay genetic risk loci converged on myelination and ATP metabolism-related modules in the proteome and transcriptome, consistent with their neuropathological relevance. Collectively, these findings reveal dynamic aspects of protein regulation in the human prefrontal cortex, providing new insights into development, maturation and disease.

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