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.
09/2021 - Development
Inheritance and flexibility of cell polarity: a clue for understanding human brain development and evolution
Cell polarity is fundamentally important for understanding brain development. Here, we hypothesize that the inheritance and flexibility of cell polarity during neocortex development could be implicated in neocortical evolutionary expansion. Molecular and morphological features of cell polarity may be inherited from one type of progenitor cell to the other and finally transmitted to neurons. Furthermore, […]
04/2021 - Frontiers
The neocortex is the largest part of the cerebral cortex and a key structure involved in human behavior and cognition. Comparison of neocortex development across mammals reveals that the proliferative capacity of neural stem and progenitor cells and the length of the neurogenic period are essential for regulating neocortex size and complexity, which in turn […]
10/2020 - Neuron
Serotonin Receptor 2A Activation Promotes Evolutionarily Relevant Basal Progenitor Proliferation in the Developing Neocortex.
Evolutionary expansion of the mammalian neocortex (Ncx) has been linked to increased abundance and proliferative capacity of basal progenitors (BPs) in the subventricular zone during development. BP proliferation is governed by both intrinsic and extrinsic signals, several of which have been identified. However, a role of neurotransmitters, a canonical class of extrinsic signaling molecules, in […]
08/2020 - Trends in Neuroscience
The evolutionary expansion of the neocortex is thought to be largely the consequence of an increase in the proliferative capacity of a specific class of neural progenitors called basal progenitors (BPs). Here we propose that BP morphology is a key cell biological feature underlying the increase in BP proliferative capacity. During neocortical expansion, BPs show […]
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.