Patterning of highly evolved neuronal circuits by protein synthesis in space and time

Matthew L. Kraushar, PhD, MD

October 11, 2021

Background


The evolutionary advance of brain structure and function is driven by the diversity of its principal cell type - neurons. The gene expression program driving stem cells to form highly diverse neuronal subtypes is the blueprint for brain circuits during development. Along with the evolution of the brain itself, gene expression has evolved to encode neuronal position, morphology, connectivity, and signaling. Defining the brain’s developmental gene expression program has been a central challenge for neuroscience, and key to understanding how the brain evolved its unique structure and function.


The final critical gatekeeper of gene expression is mRNA translation into protein by the ribosome – only recently appreciated as a modulator of neuronal differentiation, synaptic signaling, and neurological disease. Unlike transcription, protein synthesis is subcellularly targeted by ribosome localization in neuronal compartments, including dendrites, axons, and synapses where translation responds to local circuit signals. Importantly, translation can amplify or suppress gene expression by selective protein synthesis from the mRNA pool, and is faster and more scalable than transcription by orders of magnitude. While transcription analysis has been a major focus in recent years, technical challenges have limited our understanding of translation in the brain, and represents a major frontier in the field.


The focus of these IMPRS projects is how spatially targeted and precisely timed protein synthesis constitutes a kinetic gene expression program of neurodevelopment. Our hypothesis is that neurogenesis in the neocortex evolved a translation-driven gene expression program on top of a broad transcriptome, encoding the diversity of neurons from a multipotent stem cell pool in development.

 

Project 1. Click chemistry capture of the neuronal lineage-specific proteome

Our recent work indicates that the transcriptome is dynamically translated into protein during neocortex development. Project 1 will utilize metabolic protein pulse labeling during the birth of distinct neuronal lineages to capture the temporally resolved transcriptome and proteome.

 

Project 2. Single cell analysis of protein synthesis in brain development

Our recent research found that neurons activate distinct protein synthesis levels during neurogenesis in the brain. Project 2 will develop single-cell sequencing technologies targeting ribosomal complexes in the developing brain.

 

For more information, see the website of the High-Resolution Neurogenetics Group.

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