Towards improved understanding of neuroglobin's significance in cytoprotection and neurodevelopment using overexpression and knockout models
5 October 2018
UAntwerp, Campus Drie Eiken, Building Q, Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk (Antwerp) (route: UAntwerpen, Campus Drie Eiken
4:30 PM - 6:30 PM
Sylvia Dewilde, Peter Ponsaerts
PhD defence Evi Luyckx - Department of Biomedical Sciences
To design therapeutic strategies to treat nervous system related injuries and diseases, the understanding of homeostasis in the brain has been of great value. Eighteen years following the discovery of neuroglobin (Ngb), an oxygen-binding protein that is predominantly expressed in neurons of the central and peripheral nervous system, this protein is considered to promote neuroprotection by multiple cytoprotective actions of which the exact mechanisms remain elusive. To further elaborate on Ngb’s functional significance and modes of action, a plethora of Ngb overexpressing and Ngb deficient models has been created. While Ngb overexpression models point at Ngb’s cytoprotective capacities, Ngb deficient models only partially confirm the latter. Moreover, in vitro Ngb deficient studies already indicated a role of Ngb during neurodevelopment. As the level of Ngb expression, either physiologically, overexpressed or downregulated might alter its functional properties, targeting Ngb through different research approaches is essential in order to elucidate its functional significance.
First, we evaluated the therapeutic potential of Ngb overexpression in an acute and chronic mouse model of ischemic heart disease. Ngb proved to act cytoprotectively during myocardial infarcts in the acute setting while this effect was less pronounced in a chronic setting of advanced atherosclerosis. The exact conditions concerning the type and severity of the insult to elicit Ngb’s protective actions remain elusive.
In a second part, we further investigated the regulatory role of Ngb in neural stem cell (NSC) growth and proliferation using Ngb knockout (NgbKO) models. In a first study, the loss of Ngb in an in vitro NgbKO model of NSCs in 2D monolayer cultures appeared to affect CDKN1A/CDK6 expression resulting in enhanced proliferation of NSCs. In line with previous studies, these data confirmed a role of Ngb in neurodevelopment. Second, we extended our findings by creating an NgbKO mouse model and investigating the effect of Ngb deficiency in embryonic brain derived NgbKO-NSCs in both 2D monolayer and 3D neurosphere (NSPH) cultures and in vivo adult neurogenesis. This combined approach of in vitro and in vivo research strategies provided new insights in the field of neurodevelopment reflected by the impact of Ngb on NSC proliferation and growth, inherently dependent on the experimental model and setup.
In conclusion, considering Ngb’s multiple biological activities dependent on a plethora of specific conditions and stimuli, unravelling Ngb’s functional significance will remain to be challenging in the near future.