Title: Neural stem cell biology
Funder: The Francis Crick Institute

Abstract: We study how the different types of cells that constitute the nervous system are generated at appropriate times and locations to form functional neural circuits. We address these questions using the embryonic and adult mouse brain and human neural cultures – including brain organoids - as our main experimental models. Our aim is to identify fundamental mechanisms that underlie the generation and functioning of the nervous system, and to contribute to the development of therapies to treat neurological disorders. The main cellular components of the nervous system, neurons and glial cells, are generated by common progenitors or stem cells, located in specialised cell layers found throughout the embryonic brain and in restricted locations in the adult brain. The choice of stem cells to divide, remain quiescent or differentiate into neurons or glial cells, is dictated by extracellular signals including morphogens such as Wnts or BMPs, and, in the adult brain, by neurotransmitters that provide feedback signals from surrounding neuronal networks. We are interested in how stem cells integrate these multiple signals to select appropriate behaviours. Although each brain region contains many different types of neurons and glial cells connected in highly specialised circuits, each stem cell usually produces only one type of neuron or glia at a particular time and place. We identify transcription factors that allow stem cells to select a particular fate and we study the mechanisms that control the precise timing of their expression and activity, including epigenetic mechanisms that control the accessibility of regulatory elements to transcription factors. Mutations in subunits of chromatin remodeling complexes are responsible for neurodevelopmental disorders including syndromic and non-syndromic intellectual disabilities. We introduce these mutations in human neural cultures to characterize the resulting developmental defects and understand the mechanisms associated with these pathologies. The transcription factors that specify stem cell fates often also induce the differentiated phenotype of the neuronal progenies. We investigate the mechanisms that control the switch of activity and change of downstream targets of transcription factors between progenitors and differentiating neurons. We also study the gene expression programmes induced by transcription factors in differentiating neurons, and the mechanisms responsible for the sequential expression of their targets and the progressive acquisition of the neuronal phenotype. As neurons differentiate, they leave the stem cell layers where they were born and migrate to locations where they wire with other neurons and establish circuits. Neuronal migration requires the precise regulation of a large number of genes involved in cytoskeleton remodelling as well as the monitoring of environmental cues that allow neurons to follow defined routes. We study the gene regulatory programme controlling neuronal migration and its modulation by extrinsic signals that direct the migration of neurons.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL