Prof. Nael Nadif Kasri, Radboud University

Title:
Looking at neurodevelopmental disorders through the lens of evolution: a role for the autolysosomal pathway

Abstract:
  In humans, the protracted period of corticogenesis supports advanced cognition but also increases vulnerability to neurodevelopmental disorders (NDDs). Compared to other mammals, human brain development is characterized by slower, more extended maturation, with prolonged windows of neural plasticity and circuit refinement. While the overall sequence of neurodevelopment is largely conserved across species, this uniquely protracted trajectory in humans enables prolonged brain growth and complex network specialization. Recent research has highlighted the importance of human-specific genetic modifications, such as single nucleotide variants (SNVs), in driving these extended developmental programs.
  In this seminar, I will present our research on a sapiens-specific SNV located in a regulatory region of a gene linked to neurodevelopmental disorders. Using CRISPR/C9 technology, we generated isogenic induced pluripotent stem cell (iPSC) lines carrying either the ancestral SNV or disease-causing mutations. Through detailed cell biological and electrophysiological experiments in iPSC-derived neurons and brain organoids, we examined how these mutations alter neuronal development. Our findings implicate autolysosomal function as a key determinant of brain evolution and development, revealing significant changes in the pace of neuronal maturation. This work deepens our understanding of the genetic and cellular mechanisms that shape the uniquely slow, protracted neurodevelopmental trajectory of modern humans.