TY  - THES
T1  - The impact of SoxE transcription factors on the development of neural crest derivatives
A1  - Reiprich,Simone
Y1  - 2010/08/31
N2  - In recent years, Sox transcription factors have come under increasing scrutiny as important regulators of diverse developmental processes. Members of the subgroup E of Sox proteins emerged as indispensable modulators through all stages of neural crest cell development. This study adressed the impact of the two SoxE proteins Sox10 and Sox8 on the development of adrenal chromaffin cells and myelinating Schwann cells as two prominent neural crest derivatives.
During development of the adrenal gland, Sox10 and Sox8 were co-expressed in neural crest cells giving rise to the adrenal medulla. Whereas Sox8 expression declined with ongoing development, Sox10 persisted at least until birth. Sox10 deficiency in mice resulted in a complete loss of the chromaffin cell population due to increased apoptosis of neural crest cells prior to immigration into the adrenal anlagen. Sox10-deficient cells already lacked Sox8 expression before dying apoptotically, arguing that Sox10 regulates Sox8 in this cell type. In contrast, loss of Sox8 did not affect Sox10 expression. Because of functional redundancy and compensation by Sox10, loss of Sox8 was without phenotypic consequence in the corresponding mouse mutant. When Sox8 was expressed instead of Sox10, it rescued half of the chromaffin cell population indicating that Sox8 is partly capable of replacing Sox10 if its expression can be maintained in the absence of Sox10. The analysis of hypomorphic Sox10 mouse mutants additionally revealed the importance of an intact dimerization domain and the conserved K2 domain for the generation of chromaffin cells in appropriate numbers. The early loss of chromaffin cells in all mutants demonstrated the essential importance of Sox10 for survival at this developmental stage.
In Schwann cells, Sox10 was already identified as a key factor for specification and was additionally implicated in terminal differentiation and myelination. Sox10 induced expression of Krox20 as the master regulator of myelination through activation of the MSE, an enhancer downstream of the Krox20 gene. Seven high-affinity binding sites existed for Sox10 in the MSE and contributed to Sox10-dependent transactivation. Sox10 functioned synergistically with Oct6. For synergism, the DNA-binding domain of Sox10 was necessary as were the transactivation domain and the conserved K2 domain. Oct6 on the other hand required the DNA-binding POU domain but not the transactivation domain. The importance of the K2 domain for induction of Krox20 was also demonstrated in vivo in a hypomorphic mouse mutant where Schwann cells expressed a Sox10 protein without K2 domain. In these mice, Schwann cells failed to initiate expression of Krox20 despite Oct6 expression. This proved that Sox10 is indispensable in Schwann cells for terminal differentiation and myelination.
KW  - Transkriptionsfaktor
KW  - Entwicklungsbiologie
KW  - Neuralleiste
CY  - Erlangen
PB  - Universitätsbibliothek der Universität Erlangen-Nürnberg
AD  - Universitätsstraße. 4, 91054 Erlangen
L2  - http://www.opus.ub.uni-erlangen.de/opus/volltexte/2010/1958
ER  -