Interrogating the gene regulatory code – unraveling human neocortex expansion

• Applicant: Dr. Mareike Albert
• Subject Area: Developmental Neurobiology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413269590

The neocortex is considered to be the seat of higher cognitive functions in humans. During its evolution, most notably in humans, the neocortex has undergone considerable expansion, which is reflected by an increase in the number of neurons. The generation of neurons during development is the result of balanced proliferative and differentiative divisions of neural stem and progenitor cells. Differences in the proliferative capacity, the abundance of neural progenitor subtypes and their lineage relationships are thought to underlie interspecies differences in both neuron number and neocortex size. Specifically, one progenitor type, the basal radial glia, is particularly abundant in mammals with a large, folded neocortex and is characterized by extensive self-renewal and proliferative capacities. Transcriptome studies in different mammalian species have uncovered gene expression signatures underlying neocortical progenitor behavior, yet the gene regulatory mechanisms orchestrating specific gene expression programs from the genomic DNA remain poorly understood.Epigenetic mechanisms play a pivotal role in orchestrating the behavior of different cell types during development. Chromatin modifiers of the Polycomb group of proteins were shown to regulate several different aspects of neocortex development. To address the mechanism underlying cell type- and stage-specific phenotypes, (1) I will dissect the specific functions of Polycomb group Cbx proteins, for which five paralogous genes exist in mammals. Comparative analysis between mouse and human will provide insights into the role of Cbx proteins in regulating the proliferative capacity of neocortical progenitor cells.Moreover, for the developing mouse neocortex, I have generated cell type-specific epigenome profiles and established CRISPR/Cas9-based epigenome editing in vivo, which allows to interrogate the role of histone methylation at specific loci in their native genomic context. In the future, (2) I propose to expand the toolbox for in vivo epigenome editing to address fundamental questions of epigenetic gene regulation during neurogenesis. Specifically, the tools we be applied to dissect the role of histone modifications at important neurodevelopmental genes and to test the contribution of epigenetics to species-specific gene expression.In addition, (3) I propose to map enhancers active in different progenitor sub-types from the mouse and human developing neocortex. Enhancers specific to the highly proliferative human basal radial glia, which may have contributed to the evolutionary expansion of the neocortex, will be functionally characterized. This will be done using human 3D cerebral organoids, which represent a novel model system enabling functional studies of human neocortex development in vitro.This work will provide new insights into gene regulatory mechanisms with implications for neocortex development and evolution, neural stem cell regulation and neuropathologies.

• DFG Programme: Independent Junior Research Groups