Abstract
Stem cells have a high potential for replacement and transplantation in regeneration of
destroyed tissue in the body. To take advantage and benefit from this capability, one
needs to understand the development of the body and the molecular mechanisms by
which stem cells give rise to progenitor cells from which fully differentiated cells
develop. With this knowledge, it will be easier to generate the correct cells for future
transplantations. The achievement of stem cell therapy is coming closer with the new
technique to induce pluripotent cells from human somatic cells.
The neural crest provides a fascinating tool to study stem cells in development. The
neural crest stem cells are invasive, and after delamination from the neural tube they
migrate throughout the body to reach their postmigratory sites where they finally
differentiate. Among neural crest derivatives are the pheripheral nervous system,
including sensory and autonomic neurons and Schwann cells, the cardiac outflow
tract, the craniofacial skeleton and cartilage, and melanocytes.
This thesis addresses two questions: First, the role of Smad4 in neural crest
development, and second, the intracellular mechanism of neural crest stem cell
maintenance. Therefore the results (including the discussion) are given in two parts.
The first part describes the role of Smad4 in neural crest development. Canonical
TGF-β family signaling relays on the Smad transcription factor family. It was
previously shown that in cell culture, TGF-β directs neural crest cells to become
smooth muscles cells, while another TGF-β family member, BMP, drives neural crest
cells to autonomic neurons. It was found that Smad4, which is downstream of TGF-β
and BMP, has neural crest lineage-specific roles. Survival of smooth muscle cells
lining the pharyngeal arch arteries is dependent on Smad4 signaling, as is the
generation of the cardiac outflow tract. Unexpectedly, the Ngn1 and TrkA sensory
lineage in the trigeminal ganglia depends on BMP-Smad signaling. Interestingly,
however, maturation of autonomic neurons was found not to rely on canonical BMP
signaling. Instead proliferation was decreased in Smad4-deficient autonomic
progenitors.
The second part of the thesis is on potential intracellular mechanism underlying
maintenance of neural crest stem cells by the growth factors Wnt and BMP. The
canonical Wnt and BMP pathways are involved in neural crest stem cell maintenance,
but this role could not be confirmed in vivo. Furthermore, several interesting genes
regulated by Wnt and BMP treatment were identified in a gene expression analysis.
Among these genes were Ids, Cxxc5 and Zcchc12.
Büchmann-Moller, S