Molecular Mechanisms that Initiate Apical Dendrite Development During Embryonic Neuronal Development

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Molecular mechanisms that initiate leading process and apical dendrite polarization during embryonic neuronal development An early and essential event in mammalian embryonic brain development is neuronal polarization, in which distinct axonal and dendritic compartments are formed. Axons and dendrites 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. Aberrations in neuron polarization lead to developmental neuropathologies, intellectual disability, epilepsy, autism spectrum disorders, and neuropsychiatric pathologies. Bipolar polarity establishment in postmitotic neocortical and hippocampal CA1 pyramidal neuron progenitors marks polarization of the axon and the apical dendrite. The apical dendrite will develop from the leading process of the bipolar neuron whereas the trailing process will become the axon. Specification of the axon has dominated studies on neuron polarization, yielding an understanding of the mechanisms underlying axonal identity, its specification and growth. Much effort has also been directed towards elucidation of the mechanisms that control later events in dendrite morphogenesis - growth, branching, and structural plasticity. However, the events leading to bipolar polarity and the subsequent development of the apical dendrite, have remained elusive. We propose that distinctly higher cyclic GMP (cGMP) generated via localized assembly of a cGMP production machinery at the leading edge of developing pyramidal neurons, promotes bipolar polarity, leading process formation, and apical dendrite development. Using state of the art lifetime decay FLIM-FRET cGMP measurements in mouse developing pyramidal neurons in acute slice, combined with cutting edge genetic manipulations, and localized, directed optogenetic manipulations of cGMP production, this study is designed to determine the spatio-temporal regulation of cGMP during polarity establishment and apical dendrite development, and to identify its mechanistic basis in developing pyramidal neurons in vivo. Our studies will provide important advance in the understanding of the early molecular events that take place during axon and apical dendrite establishment in principal excitatory neurons in the rodent brain, and will contribute to the identification of molecular targets and development of therapeutics for developmental neuropathologies resulting from abnormal axon and dendrite development.