Martínez Chávez, Erick Ariel: The role of the zinc finger transcription factor Gli3 in murine hindbrain development. - Bonn, 2019. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5n-55056
@phdthesis{handle:20.500.11811/8034,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5n-55056,
author = {{Erick Ariel Martínez Chávez}},
title = {The role of the zinc finger transcription factor Gli3 in murine hindbrain development},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2019,
month = jul,

note = {The zinc finger transcription factor GLI3 is a downstream component of the Sonic Hedgehog signaling pathway and functions mostly as a transcriptional repressor. GLI3 is required for the proper development of dorsal forebrain, dorsal midbrain and cerebellum. In contrast, the function of GLI3 in the development of the posterior dorsal hindbrain is not well understood. Precerebellar mossy fiber and climbing fiber neurons (MFNs and CFNs) provide afferent input into the cerebellum and arise from progenitor pools at the dorsal edge of the posterior embryonic hindbrain, the caudal part of the lower rhombic lip (clRL). These neurons follow well defined migratory routes before settling at different axial levels in the hindbrain. Previous studies demonstrated that precerebellar migratory streams are disrupted and precerebellar nuclei are disorganized in Gli3 null mutant mice (Gli3 extra toe; Gli3xt/xt). This thesis dissects how GLI3 influences the development of the murine precerebellar system and investigates the function of GLI3 in non-precerebellar structures in the developing posterior hindbrain. The analysis of Gli3xt/xt embryos at different embryonic stages shows that precerebellar progenitors are properly established in the clRL of Gli3xt/xt embryos, but the generation of a subpopulation of CFNs is compromised. Moreover, the migration of MFNs is severely altered: the onset of migration in MFNs that remain in the posterior hindbrain (posterior extramural stream) is delayed and the MFNs migrating anteriorly (anterior extramural stream; AES) fail to assemble into a compact migratory stream. Moreover, the subset of AES neurons arising from the most posterior part of the clRL fails to migrate anteriorly and settles at ectopic posterior positions. Aside from the defects in precerebellar system development, the only other alteration in the hindbrain of Gli3xt/xt mutants uncovered in this study was a change in neurotransmitter phenotype in neurons of the spinal trigeminal nucleus. To investigate whether GLI3 plays a cell- or non cell-autonomous role in precerebellar neurons, Gli3 was conditionally inactivated either in all MFN progenitors or in the central nervous system (CNS) after embryonic day 10.5. In these conditional gene inactivation models, the precerebellar system developed normally, suggesting that the function of GLI3 in precerebellar development is not cell-autonomous and may even be outside of the CNS. Analysis of cranial ganglia and their projections in Gli3xt/xt embryos revealed an increased size of the trigeminal ganglion and a severe disorganization of its central descending projections, the spinal trigeminal tract (sp5). Neurons of the AES were in close contact with the sp5 during their anteriorly-directed migration in control embryos, while the AES-sp5 interactions were disrupted in Gli3xt/xt mutants. Thus, the normal development of the sp5 requires GLI3 function and might be a prerequisite for correct AES migration. These results point to a novel mechanism in precerebellar migration, but further studies will be necessary to investigate whether and how the sp5 acts as a guiding structure for precerebellar migration, and which other hindbrain nuclei and projections influence precerebellar migration.},
url = {https://hdl.handle.net/20.500.11811/8034}
}

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