Mechanisms of cortical neurogenesis

Development of the mammalian cortex starts with the exponential expansion of self-renewing stem cells called neuroepithelium cells (NE), which subsequently differentiate into the radial glia that are responsible for producing neurons and themselves by asymmetric divisions. Later, the progenitor pools are depleted by terminal divisions that generate astroglia. Given that brain size is unique for each species, the developing brain must tightly and genetically regulate the switching of cell division modes from an exponential expansion phase (symmetric division with daughters like the mother) to a linear expansion phase with asymmetric division and finally to terminal divisions that deplete the progenitor pool. How then do the stem cells know the right number of times to carry out each mode of cell division? What mechanisms transform self-renewing NE cells into RG cells capable of generating neurons? Is it possible to turn the biological clock backwards to produce self-renewing NE cells from endogenous cells like glia from the adult brain, providing a source of neurogenic progenitors? And further, how do all of the differentiation processes affect the size of cortical structures and their functions as seen in brain size changes during evolution? Do animals with expanded cortical areas show improved performance? Or does increased cortical size result in pathogenic conditions such as macrocephaly or autism? We will answer these questions by analyzing factors that confer expansive or neurogenic characteristics upon cortical progenitors, and those regulating the transition of the differentiation process.

Mammalian neocortex is composed of hundreds of different types of neurons and glia. NEs are multipotent progenitors generating all types of cortical pyramidal neurons found in all cortical layers. After differentiated into RG, the progenitors progressively generate distinct pyramidal neurons over time as deep layer neurons and subsequently upper layer neurons. The multipotency of cortical progenitors that can generate types of neurons in all layers is progressively restricted during embryonic stages. However, the molecular mechanisms that turn on the cascade of sequential specification of progenitors, and in particular what triggers the decrease in competency of progenitors, remains unknown. We will address these questions using various approaches (single cell gene expression analysis, human ES/iPS cells) to elucidate transcriptional codes in cortical progenitors that determine cortical neuronal fates, and apply these findings to develop a better understanding of psychiatric disorders such as autism, schizophrenia and bipolar disorders.

The mammalian brain is an organ that is unable to regenerate due to its poor neurogenic capacity. As such, brain injuries such as stroke and neurodegenerative disorders have a huge effect on our quality of life. Our study aims to identify signalling pathways that can convert resident cells in the brain to neural progenitors in order to replenish the lost neurons in damaged brains. We particularly focus on signaling pathways that are able to convert cortical glia into progenitor states in order to replenish an adequate number of neurons/glia, and also be competent in generating various types of neuronal and glial populations. With our findings, we aim to establish a firm foundation for brain repair following injury such as stroke and degenerative disorders, including Alzheimer’s disease.