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Transl Psychiatry. 2018 Dec 5;8(1):267. doi: 10.1038/s41398-018-0306-4.

Temporal proteomic profiling of postnatal human cortical development.

Author information

1
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. michael.breen@mssm.edu.
2
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. michael.breen@mssm.edu.
3
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. michael.breen@mssm.edu.
4
Department of Chemical Engineering and Biotechnology, University of Cambridge, CB3 0AS, Cambridge, UK.
5
Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, BD2K-LINCS Data Coordination and Integration Center, Knowledge Management Center for Illuminating the Druggable Genome (KMC-IDG), Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
6
Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg Germany, Freiburg, Germany.
7
Stanley Medical Research Institute, Laboratory of Brain Research, Rockville, MD, 20850, USA.
8
Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW, 2031, Australia.
9
School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia.
10
Department of Neuroscience & Physiology, Upstate Medical University, Syracuse, NY, 13210, USA.
11
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
12
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
13
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Abstract

Healthy cortical development depends on precise regulation of transcription and translation. However, the dynamics of how proteins are expressed, function and interact across postnatal human cortical development remain poorly understood. 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 < 5%). Network analysis identified three modules of co-regulated proteins correlated with age, including two modules with increasing expression involved in gliogenesis and NADH metabolism and one neurogenesis-related module with decreasing expression throughout development. Integration with paired transcriptome data revealed that these age-related protein modules overlapped with RNA modules and displayed collinear developmental trajectories. Importantly, RNA expression profiles that are dynamically regulated throughout cortical development display tighter correlations with their respective translated protein expression compared to those RNA profiles that are not. Moreover, the correspondence between RNA and protein expression significantly decreases as a function of cortical aging, especially for genes involved in myelination and cytoskeleton organization. Finally, we used this data resource to elucidate the functional impact of genetic risk loci for intellectual disability, converging on gliogenesis, myelination and ATP-metabolism modules in the proteome and transcriptome. We share all data in an interactive, searchable companion website. Collectively, our findings reveal dynamic aspects of protein regulation and provide new insights into brain development, maturation, and disease.

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