Project Details
Projekt
Timed nucleolar shutdown restructures the developing brain genome
Subject Area
Developmental Neurobiology
General Genetics and Functional Genome Biology
Molecular Biology and Physiology of Neurons and Glial Cells
General Genetics and Functional Genome Biology
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 563470554
The brain is constructed from many varieties of neurons born from neural progenitors in the embryo. An immense variety of neurons forms the neocortex, an evolutionarily advanced brain region specific to mammals. The mechanism that specifies different neuronal subtypes in the neocortex remains unresolved, but the timed regulation of gene expression in the nucleus is a key mechanism controlling neuronal identity. Our SPP 2502 project is motivated by a striking example of precisely timed genome deactivation and restructuring discovered in our preliminary data. We find that the nucleolus, a distinct compartment of DNA coding for ribosomal RNA in the nucleus, rapidly decreases activity and disassembles within a 24-hour window of the 7-day period of mouse neocortex neurogenesis. Nucleolus shutdown is accompanied by the restructuring of DNA, which relocalizes to the nucleus periphery, known as the lamina. We hypothesize that this sharp change in nucleolus activity redirects neuronal fate by changing genome structure and consequently gene expression activity. Our approach employs two new technologies to target this developmental window: labeling gene expression in action in the live embryo, and tracking genome structure in the nucleus at single-cell resolution. The first objective is to track large-scale genome relocalization from the nucleolus to the nuclear lamina, along with changes in gene expression activity in single-cells. The second objective is to pinpoint how large-scale genome relocalization is reflected in the 3D restructuring and modification of chromatin. The third objective is to manipulate nucleolus activity in the neocortex in vivo, by prematurely inactivating it, or ectopically prolonging its activity, to directly measure its impact on neuronal fate. To accomplish these objectives, our team is a unique combination of three labs, with expertise in neocortex gene expression control, genome structure and modification, and advanced single-cell bioinformatics. Taken together, our project will discover how timed nucleolus activity is an anchor for genome structure, control switch for gene expression, and driver of neuronal fate in neurodevelopment.
DFG Programme
Priority Programmes
