I. The origin and evolutionary processes of the neocortex

The dorsal region of the vertebrate telencephalon, called the pallium, arises as a homologous region in all amniotes. However, the brain structures derived from the pallium are extremely diverse among animal groups. In mammals, the pallium is significantly enlarged and a six-layered structure is constructed. On the other hand, in Lepidosauria, such as lizards and geckos, and Archosauria, such as turtles, crocodiles, and turtles, the pallium does not expand and a three-layered structure or neuronal core structure is formed (Nomura et al. Journal of Experimental Zoology 2013; Neuroscience Research 2014).

These diverse brain morphologies are presumably due to differences in the timing of neural stem/progenitor cell proliferation and differentiation, as well as spatial and temporal control mechanisms of neuronal subtype specification and migration patterns. On the other hand, even if diverse as complete products, they may share some parts or components of the blueprint, and these features may be traits inherited from the common ancestor of amniotes (Nomura et al. PLoS One 2008; Nature Communications 2013; Development 2016; Yamashita et al. Development 2018; Cell Reports 2018; Cell Reports 2020; Nature Communications 2022). We hope to elucidate the molecular mechanisms that led to the expansion and layering of the cerebral cortex through comparative molecular developmental analysis of amniotes.

II. Evolutionary Developmental Analysis of Human-Specific Phenotypes

Current humans have unique anatomical features, such as a skeletal system adapted for bipedal walking and a significantly enlarged cerebrum. How did these unique human phenotypes evolve? To answer this question, we are focusing on the genomic and genetic changes that have occurred during human evolution and their impact on the phenotype through comparative developmental approaches and the generation of genetically engineered mice. We have generated knock-in mice with extinct Neanderthal and Denisovan-specific amino acid substitutions in the GLI3 gene and found that these polymorphisms induce morphological changes in the skull and vertebrae (Agata et al. Frontiers in Cell and Developmental Biology 2023). Elucidation of the molecular mechanisms that gave rise to the uniqueness of the human phenotype will not only shed light on the history of human evolution from a biological perspective, but also help to elucidate the pathogenesis of various human diseases.

As a basis for promoting such evolutionary developmental research, we have established in vitro and in vivo embryonic manipulation and gene transfer techniques (Nomura and Osumi, Development 2004; Nomura et al. Development 2006; Frontiers in Neuroscience 2015), and have conducted genetic analysis of stem cell lineages analysis (Nomura et al. Cell Stem Cell 2010; Cell Reports 2018).