- Awarded: 2017
- Award Type: Pilot
- Award #: 507047
Cellular function is intimately linked to subcellular architecture. Within a dividing cell’s dynamic mitotic spindle or a neuron’s complex dendritic arbor, cellular architecture is largely governed by cytoskeletal networks. It is therefore essential to understand the regulatory mechanisms underlying the development, modifications and maintenance of the cytoskeletal internal structure, because alterations of these processes can disrupt cell function and ultimately lead to cell pathology.
Recurrent disruptive mutations in a Down syndrome critical kinase, MNB/DYRK1a, are correlated with sporadic cases of autism spectrum disorders (ASD) with associated microcephaly. However, it is unknown how these ASD mutations alter MNB/DYRK1a function and lead to pathological conditions. Kassandra Ori-McKenney hypothesizes that mutations in the MNB/DYRK1a pathway may lead to the development of ASD by affecting neuronal morphogenesis and neural progenitor proliferation. To assess this, Ori-McKenney’s team at the University of California, Davis, plans to dissect the role of the MNB/DYRK1a kinase pathway in regulating the cytoskeleton.
To approach this problem, the Ori-McKenney lab will employ a suite of in vivo and in vitro techniques in Drosophila melanogaster. Using a chemical genetic approach combined with state-of-the-art mass spectrometry, they plan to identify direct downstream substrates of MNB/DYRK1a, then characterize which of these targets is involved in neuronal morphogenesis and proliferation. In addition, they will analyze the effect of ASD point mutations on the biochemical and cell biological functions of MNB/DYRK1a. Finally, they will investigate the localization and function of MNB/DYRK1a throughout the cell cycle both ex vivo and in vivo, in order to understand how loss of MNB/DYRK1a causes microcephaly and the intellectual disability manifested in ASD.
This proposal will address the roles of the MNB/DYRK1a pathway during neuronal morphogenesis and mitosis, and determine how MNB/DYRK1a mutations associated with ASD alter these roles. Overall, the results of these aims will provide novel insights into how MNB/DYRK1a contributes to ASD on a molecular and cellular level.