Dr Setsuko Sahara
Phone: 0207 848 6562
For publications etc., see lab members below .
New (updated April 2014): A Leverhulme-funded postdoctral position will be available soon in the lab of Dr Sahara at the MRC Centre for Developmental Neurobiology. Please feel free to contact me with any questions regarding this position by e-mail.
We are focused on the development of the mammalian neocortex, which is the control centre of our behavior, thought and intellectual abilities. The neocortex is composed of hundreds of different types of neurons and glia, and decoding the mechanisms regulating the self-renewal capacity and competency of cortical progenitors is crucial to understanding:
1) how our brains undergo healthy development and what happens to the brain in psychiatric disorders, and
2) how we could develop novel strategies to regenerate damaged nervous system.
Current main projects in the group are as follows:
1) Identify determinants that confer expansive or neurogenic characteristics to cortical progenitors
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.
2) Transcriptional identity in cortical progenitors generating diversity of the cortical neurons
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.
If you are interested in our research and looking for an opportunity to join our group as a graduate student or post-doc, please contact Setsu by e-mail with your resume/CV and the names and contact information of 2-3 referees.