Neocortical neurons show admirable diversity in function, transcriptional programs, dendritic morphology and axonal targets. To specify this remarkable diversity, the intrinsic molecular pathways defining transition from genome to proteome in developing neocortical neurons must be precisely regulated in space and time. RNA- binding proteins (RBPs) are known to be at the cross-road of the genome to proteome axis through the splicing, export, stabilization and translation of transcribed mRNAs. By regulating these post-transcriptional events, RBPs are implicated in control of protein expression levels and neuritogenesis by interfacing with distinct morphogen and/or trophic extracellular signals. Bound mRNAs can include distinct subsets of transcribed mRNAs and form what we call "RNA-operons". These RNA-operons also respond to external cues providing immediate translation to protein, allowing for rapid adjustments of protein levels for a crucial cellular event. These RNA-operons then respond to environmental signals allowing prompt translation of the given mRNA to protein necessary for a particular cellular event. We identified a neocortical RNA-operon that consists of an RBP that binds six neocortical mRNAs characterized by forkhead transcription factor domains at least five days before their translation. To the best of our knowledge this is the first evidence that an RBP binds a subset of six forkhead mRNAs in any system, including developing neocortex. Moreover, we identified a thalamic morphogen signal that affects the phosphorylation state of this neocortical RBP and increases the protein levels of a neocortical forkhead transcription factor. This cascade of events happens before neocortical neurons finish their neurite development. Indeed, both neocortical RBP and thalamic morphogen affect neocortical neuritogenesis. Therefore, our central hypothesis is that this mechanism of thalamic morphogenic regulation of neocortical RNA-operons is crucial for the spatiotemporal specification of subtypes of neocortical neurons and their neurite differentiation. Therefore, we will determine (1) the mechanisms of the neocortical RNA operon in the specification of neocortical projection neurons and their dendrite differentiation;and (2) the role of a thalamic morphogen on neocortical RNA-operon-dependent specifications. To do this, we will use an elegant combination of neuroanatomical, cellular, molecular and genetic approaches. Findings from this proposal will provide previously unrecognized molecular mechanisms of post-transcriptional control in the overall specification of subtypes of neocortical neurons that may open new avenues for treatment of distinct neurodevelopmental disorders.
Many neurological and psychiatric disorders are increasingly associated with disruption of projection neurons of the neocortex, such as schizophrenia. Although we know that the proper function of neocortical projection neurons is disturbed in these many devastating disorders, there are no effective therapies to restore their appropriate function. For these therapies to work, we need to know more about the intrinsic and extrinsic molecular cues that specify subtypes of neocortical neurons. This proposal will shed light on the molecular and cellular mechanisms that control timed mRNA translation events during the specification of subtypes of neocortical projection neurons. At present, little is known about these events.
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