Controlling spatially restricted intracellular protein-activity during embryonic neuronal development using
biomagnetic nanotechnologies
During mammalian embryonic development, neuronal cells polarize to create distinct cellular compartments of the
axon and dendrite that inherently differ in the molecular composition of their cytoplasm, cytoskeleton, and plasma
membrane. These differences underlie the unique morphology and function of these compartments and are
responsible for directed information flow in the brain. Whereas axons transmit the chemical and electrical neuronal
signals, the dendrites receive and integrate them. This polarized architecture arises from precisely regulated spatial
segregation of specific intracellular proteins’ activities to discrete subcellular regions of a single neuronal cell that
respectively dictate the axonal vs. dendritic fate. Aberrations in the localization of these proteins’ activity lead to
defective neuron polarization and underlie severe human neurodevelopmental pathologies including intellectual and
motor disabilities, epilepsy, and autism spectrum disorders. The ability to exert precise spatio-temporal control on
intracellular protein-activity would permit directed regulation of neuronal polarization and may provide new
approaches for the repair of the underlying neurodevelopmental pathologies. To date, no existing technologies,
including leading molecular-genetics, light-controlled protein activation, or their combination using optogenetics,
can allow sustained spatial restriction of intracellular protein-activity in the developing neuron. The main objective
of this study is to address this fundamental challenge in neurobiology by developing biomagnetic-based
nanotechnologies that will enable the spatial and temporal control of intracellular protein function in developing
embryonic neurons. Specifically, we will develop biomagnetic-nanotechnologies to deliver and retain localized
activity of the kinase LKB1, to dictate the process of axon formation in embryonic neurons in culture. Such a
proposal demands a multi-disciplinary approach that integrates neurobiology, material engineering, and
bioelectronics, for the development of protein based neuro-therapeutics. Many cellular events that dictate cell
morphogenesis, metabolic state, or its unique physiological functions, in all cell types across evolutionarily distant
species, are determined by highly localized and timed activity of specific intracellular proteins. The causative role of a
critical intracellular protein in a particular cellular event or the ability to control that event can only be achieved by
directed subcellular localization and retention of the protein or its activity. As current methodologies for spatio-temporal
manipulation of protein function are inherently incapable of allowing the long-term spatial confinement of protein
function, our studies will be applicable to many fundamental cellular events, as polarization and migration, and to the
many intracellular proteins that control these cellular processes.
