Abstract
The development of a complex multicellular organism is dependent on the coordinated spatiotemporal generation of diverse cell types. This diversity is achieved by multipotent stem cells that give rise to a variety of differentiated and specialized cells. The control of stem cell proliferation and differentiation involves intrinsic and extrinsic factors that activate a complex network of molecular signaling pathways. Understanding the mechanisms of such signaling pathways in the context of a developing organism has become a major focus in molecular and cell
biological research. Neural stem cells are a subtype of stem cells that generate all the cells of the
nervous system and they arise from the neuroepithelium after neural tube closure but can also be
found in the adult brain. One of the most conserved signaling pathways critically involved in
maintenance of neural stem cells is the Notch signaling pathway. In my doctoral studies, I
investigated the role of several Notch signaling components in order to elucidate their impact on
neural stem cell development in the early central nervous system.
The first part of my thesis focuses on an extracellular component and a signaling modulator of the
Notch pathway. The Notch ligand Jagged1 is expressed in a specific pattern in the neural tube that
suggests a role in local neuroepithelial stem cell maintenance or neural subtype specification.
Unexpectedly, conditional ablation of Jagged1 was not observed to have any effect on
neuroepithelial stem cell proliferation or specification in vivo. Due to its complementary
expression pattern to Jagged1, the Notch signaling modulator Manic fringe was further
investigated regarding its role in neuroepithelial cell fate specification. In contrast to our
expectations, this study could not attribute any specific function to Manic fringe in neural or glial
subtype specification in the developing neural tube.
In the second part of my thesis I analyzed the role of the Notch1 receptor that is widely expressed
on neuroepithelial stem cells throughout the early developing central nervous system. Apart from
the well known role in preventing premature differentiation, I could establish a new role for
Notch1 in suppressing the precocious generation of basal progenitors, a transiently emerging cell
population that amplifies the number of neurons in the developing forebrain. It was possible to
demonstrate that this effect is uncoupled from preventing neuronal differentiation and that the
emergence of basally dividing cells upon conditional Notch1 ablation was not due to general
defects in the neuroepithelial structure or altered behavior of neuroepithelial stem cells. Notably,
ablation of Notch1 in the neuroepithelium resulted in the generation of basal progenitors also in
areas of the central nervous system that are normally devoid of such progenitors. Thus, our data
suggest that fine tuning in Notch signaling might be involved in area-specific growth of the central
nervous system.
Märki, S D