Microtubule-associated Ser/Thr kinases in health and disease

The human brain, comprising approximately 86 billion neurons, is extraordinarily complex and necessitates tight control over its development. Errors in signal transmission or delays in the timing of developmental pathways can lead to irreversible changes in brain anatomy and connectivity that give rise to neurodevelopmental disorders (NDDs) characterized by cognitive, locomotor, and behavioral dysfunction. Recently, members of the Microtubule- associated Serine/Threonine (MAST) kinases have been implicated in a spectrum of NDDs. An increasing number of patients with anatomical differences in brain development, epilepsy, autism, intellectual disability, and impairment of motor skills have been associated with mutations in four human genes that encode MAST1-4 proteins. Patient mutations in MAST1, in particular, are recurrent and have been mapped to critical parts of the MAST1 protein, including its executive function as a protein kinase. Protein kinases are critical signal transducers in cells, relaying instructions for critical cellular processes with high spatial and temporal fidelity. The structure, function, and cellular targets of the MAST kinases are all currently unknown. In order to understand the molecular basis of disease caused by mutations in these genes, it is necessary to understand what inputs these kinases respond to, how they transduce the signal into an executive output, and what effector molecules they target in the cell. We will use our expertise in structural biology and biochemistry to try to understand what is necessary and sufficient for MAST activity. In collaboration with neuroscientists at the LMU in Munich, we will investigate potential substrates of MAST identified from paired wild-type/mutant mouse models of the human NDD mega corpus callosum with cerebellar hyperplasia and cortical malformations (MCC-CH-CM). Finally, we will again employ biochemistry and structural biology to rationalize mutations in MAST associated with MCC-CH-CM. Humans encode more than 500 protein kinases, of which only a fraction have been intensively investigated. Whilst the executive function of these switches is well understood at a molecular and mechanistic level, their spatial and temporal regulation in the cell, including their substate specificities, are very poorly understood. This proposal will address these gaps in our knowledge for the MAST kinases with the potential to be able to rationalize precisely what goes wrong during brain development in MCC-CH- CM. By collaborating with neuroscientists, we will be able to transform molecular information into a cell, tissue and even organismal level understanding of neurodevelopment.