Abstracts

Two major classes of neural stem and progenitor cells (NPCs) in the developing neocortex can be distinguished. First, NPCs that reside in the ventricular zone (VZ), i.e. neuroepithelial cells, apical (or ventricular) radial glia (aRG), and apical intermediate progenitors, collectively referred to as apical progenitors (APs). Second, NPCs that reside in the subventricular zone (SVZ), i.e. basal (or outer) radial glia (bRG) and basal intermediate progenitors, collectively referred to as basal progenitors (BPs). Neocortex expansion is thought to be linked to an increased abundance and proliferative capacity of BPs.

In my lecture, I will report the following (after an introduction into the topic):

·         The human-specific gene ARHGAP11B amplifies basal progenitors.

·         This ability of ARHGAP11B depends on a single C-to-G base substitution.

·         ARHGAP11B protein is imported into mitochondria and promotes glutaminolysis.

·         ARHGAP11B can expand the primate neocortex.

·         ARHGAP11B-mediated neocortex expansion increases cognitive performance.

·         Modern human APs exhibit a longer metaphase during mitosis than Neanderthal APs.

·         Modern human APs make less chromosome segregation errors than Neanderthal APs.

·         These differences are due to 3 amino acid substitutions in KIF18a (1) and KNL1 (2).

·         Modern human vs. Neanderthal transketolase-like 1 (TKTL1) differs by just 1 amino acid.

·         Modern human, but not Neandertal, TKTL1 increases bRG and cortical neurons.

·         In fetal modern human neocortex, TKTL1 is most highly expressed in the frontal lobe.

The centrosome is the primary microtubule organizing center (MTOC) and consists of two centrioles surrounded by pericentriolar material (PCM). In vertebrates, centrioles are composed of nine triplet microtubules and are required for the formation of dynamic microtubule arrays (MTs), mitotic spindles, cilia, and flagella. Centrosomal abnormalities are thought to contribute to aneuploidy, cancer, and microcephaly, while ciliary defects are attributed to human disorders collectively termed ciliopathies, including retinal degeneration, polycystic kidney disease, Bardet-Biedl syndrome, and Joubert syndrome. Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by small brain size and mild to severe intellectual disability. Interestingly, mutations in many centrosome genes have been reported to cause MCPH, and their overexpression causes tumors. Over the past 20 years, my laboratory has identified several key centrosomal proteins, including CPAP (Nat Cell Biol 2009, Cell Rep 2016, J Cell Sci 2020, Front Cell Dev Biol 2022), STIL (EMBO J 2011), CEP135 (EMBO J 2013), CEP120 (J Cell Biol 2013, Sci Rep 2019, Genes & Dev 2021), RTTN (Nat Commun 2017) and Myosin-Va (Nat Cell Biol 2019), that are involved in centriole duplication and cilia formation. In my lab, we combine molecular and cellular, genetic, mouse models, and hiPSC-derived brain organoid approaches to elucidate how these organelles are built and how defects in centrosome genes disrupt the brain development and lead to human primary microcephaly.

The mammalian cerebral cortex is a remarkably complex organ responsible for the perception of sensory stimuli, the execution of motor actions, learning, cognition, and consciousness. To perform such complicated functions, it is compartmentalized into multiple functional units or cortical regions, including the newly evolved neocortex and evolutionarily older paleocortex and archicortex. Each cortical region has unique cytoarchitectures, patterns of gene expression, and distinct sets of input and output projections to perform specific functions. We aim to understand how neurons acquire region-specific properties during development and how boundaries are formed between cortical regions. We found that COUP-TFI, an orphan receptor expressed in a high-caudal-lateral-to-low-rostral-medial gradient in cortical progenitors, determines the size and position of the neocortex (NC) and entorhinal cortex (EC), two abutting cortical regions generated from the same progenitor lineage. Further, by inducing protocadherin 19 expression, COUP-TFI establishes a sharp boundary between NC and EC. Thus, we showed that the determination of different cortical regions and subregions relies on expression gradients of patterning transcription factors. As many neurological disorders assault specific types of neurons in specific brain regions, uncovering the mechanisms controlling cortical regional specification will contribute to the understanding of cortical dysfunction in disease states.

A rapid expansion of the cerebral cortex in size and complexity is a hallmark of mammalian evolution, leading to a folded brain. However, cortical size and complexity are highly variable across species, while all of them share a basic 6-layered structure. We have been investigating mechanisms underlying these features, using ferrets, as a gyrencephalic model that is experimentally manipulatable, with comparing with mice and humans.  We found that ferret neural stem cell subtypes and their temporal pattern are similar to those in humans while the time scale is very different (3 weeks vs. 3months). This difference in the temporal scale is more evident between mice and humans (a week vs. 3 months).  Furthermore, ferret stem cell lineages turned out to be highly variable due to the stochastic occurrence of stem cell-like sibling cells of a stem cell, in contrast to the mouse stereotyped pattern. We discuss mechanisms for each of lineage variation and temporal scaling, and a possible unifying mechanism.