The neocortex is the part of brain involved in a variety of higher cognitive functions, including language. During human brain evolution, the neocortex underwent a dramatic expansion, which is considered to be the basis for the unparalleled cognitive abilities of humans. Cognitive impairments often result from altered size or shape of the neocortex, which in turn are caused by defects during neocortex development. However, we still understand very little about the mechanisms that are at the basis of human neocortex development and the related pathologies.
The research of the Kalebic Group focuses on the molecular and cell biological mechanisms underlying human neocortex development and its implications for human evolution and neurodevelopmental disorders. We are particularly interested in the following two aspects:
- the proliferative capacity of neural stem cells, which is a key feature determining the number of produced neurons thus controlling the neocortex size. We study the molecular and cellular characteristics of neural stem cells that have led to the remarkable expansion of the human neocortex as well as the genomic mutations present in neurodevelopmental disorders which lead to an impaired neocortex size, such as microcephaly (too small brain) and macrocephaly (too large brain).
- the migration of neurons, which is fundamental for establishing the correct shape of neocortex. Defects in migration can lead to disorders that affect neocortical folding, such as lissencephaly (too few folds) and polymicrogyria (too many small folds). Using mammalian species with a smooth or folded neocortex, we investigate the mechanisms underlying the neocortical folding and the role of genes whose mutations can cause impaired folding in humans.
The Kalebic Group takes a multidisciplinary approach across biological scales, combining cutting-edge molecular and genetic techniques, CRISPR/Cas9 genome editing, advanced live imaging and computational tools. We apply these techniques to a variety of model systems, including human samples, cerebral organoids and animal models.
Genetic manipulation in the ferret brain (age: postnatal day 16). Neural stem cells in the left hemisphere were electroporated in vivo 24 days earlier. GFP+ neurons (green) have their cell bodies in the electroporated hemisphere and extend their processes to the contra-lateral hemisphere. Magenta, GFAP (glial cell marker); blue, DAPI (nuclei).
Credit: Kalebic et al., eLife 2018;7: e41241.
- 05/2020 - Journal of Visualized Experiments
Presented here is a protocol to perform genetic manipulation in the embryonic ferret brain using in utero electroporation. This method allows for targeting of neural progenitor cells in the neocortex in vivo.