PUBLICATION

Towards a molecular understanding of midbrain hindbrain neurogenesis and reward in zebrafish

Authors
Ninkovic, J.
ID
ZDB-PUB-090521-35
Date
2006
Source
Ph.D. Thesis : 195p (Thesis)
Registered Authors
Ninkovic, Jovica
Keywords
none
MeSH Terms
none
PubMed
none
Abstract
The developmental functionality of neural networks involved in complex diseases, such as addiction, is an important determinant of adult behavior. Thus, understanding the principles of embryonic neurogenesis is of prime importance. To approach this issue, I focused on neurogenesis control in the midbrain-hindbrain domain, which contains a long-lasting progenitor pool, the Intervening zone (IZ). I identified the Hairy/E(Spl) factors Him and Her5 as the crucial determinants of IZ formation. The expression of these two factors at the end of gastrulation prefigures and later during development precisely delineates in space the IZ. The IZ is formed as a two-partite area (lateral (LIZ) and medial (MIZ)), these two domains differing with respect to their sensitivity to the ``Him + Her5'' inhibitory activity. Using single and double knockdowns of him and her5, as well as a him + her5 deletion mutant background b404 , I demonstrated that Him and Her5 are equally necessary for MIZ formation, and that they act redundantly in LIZ formation in vivo. I showed that these processes do not involve cross-regulation between Him and Her5 expression or activities. Increasing the function of one factor when the other is depleted, I further showed that Him and Her5 are functionally interchangeable. My results are in agreement with a model where the global ``Him + Her5'' activity inhibits ngn1 expression in a dose-dependent manner and through different sensitivity thresholds along the medio-lateral axis of the neural plate. I showed that this differential sensitivity of the MIZ and LIZ were based on graded Gli signaling along the medio-lateral neural plate axis at the level of the IZ, and that Gli1 activity in this process was regulated by the PKA/ GSK3beta phosphorylation tandem. According to my results, Gli1 increases the threshold level for ``Him + Her5'' inhibitory activity in the MIZ and loss of Gli1 function render the MIZ into the LIZ in respect to ``Him + Her5'' inhibitory activity
Errata / Notes
Dissertation, München, Techn. University
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping