A Drosophila Model of Neuronal MECP2 Function
Final Report Abstract
The main goal of this propopal was to utilize Drosophila as a genetic model organism to study specific aspects of mecp2 induced cellular pathophysiology in the nervous system. Based on preliminary data we had hypothesized that knock down of kibra could rescue cellular and behavioral phenotypes as induced by hMECP2 overexpression in Drosophila neurons. We confirmed that hMECP2 increased kibra expression in Drosophila CNS, and we confirmed full rescue of hMECP2 induced pathophysiology by RNAi knock down of kibra in Drosophila neurons. We could also validate kibra as a target of Mecp2 in mouse brain. Therefore, we fully completed aim 1 and provided a functional link of two neuronal genes of high relevance in human health and disease. In addition, experiments in mammalian cell culture have indicated a role of S80 phosphorylation and forkhead domain transcription factors in affecting MeCP2 induced apoptosis. We confirmed these mechanisms in Drosophila in vivo, thus indicating mechanistic conservation between flies and mammalian cells and highlighting the utility of the Drosophila model for understanding specific aspects of MECP2 function (Williams et al., 2016b). Since we identified kibra is as an essential target of MeCP2 in dendritic growth regulation in Drosophila and mouse, and kibra interacts with the Hippo kinase cascade we further investigated the role of Hippo signaling in dendrite growth. We identified Merlin as an additional key signal in Drosophila motoneuron dendritic growth regulation, and as a modifier of MECP2 induced dendritic defects, but neither kibra nor Merlin regulate motoneuron dendritic development through canonical hippo signaling.
Publications
- (2014) Identification of a novel gene involved in MeCP2 related dendritic defects in a Drosophila neuronal gain-of-function model. Soc for Neuroscience Annual Meeting
Williams AA, White R, Duch C
- (2016) Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations. PLoS One 11(7):e0159632
Williams AA, Mehler VJ, Mueller C, Vonhoff F, White R, Duch C
(See online at https://doi.org/10.1371/journal.pone.0159632) - (2016) MECP2 impairs neuronal structure by regulating KIBRA. Neurobiol Dis 91:284-91
Williams AA, White R, Siniard A, Corneveaux J, Huentelman M, Duch C
(See online at https://doi.org/10.1016/j.nbd.2016.03.019) - (2019) Longitudinal assessment of health-span and pre-death morbidity in wild type Drosophila. Aging 11(6):1850-1873
Gaitanidis A, Dimitriadou A, Dowse H, Sanyal S, Duch C, Consoulas C
(See online at https://doi.org/10.18632/aging.101880)
