Systems Level Investigation of Transcriptional and Post-transcriptional Mechanisms Directing Class-specific Dendrite Morphogenesis




Chandramouli Iyer, Srividya

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Dendrites - neuronal structures that are primarily designed for information input, are one of nature's remarkable architectural feats and the elaborate and manifold growth patterns displayed by dendritic arbors raise important developmental questions. The particular shapes of dendrites are not only hallmarks of neuronal identity but are also crucial in neuronal function and circuit assembly as they influence the range of inputs received by a neuron and thereby, the processing and integration of electrical signals. Therefore, insights into mechanisms underlying the developmental origins of arbor shape will shape our understanding of how the nervous system functions and take us closer to identifying the underlying causes of several neurological and neurodevelopmental disorders. 
 During the past two decades, studies in Drosophila melanogaster have identified mechanisms of dendrite morphogenesis with great potential for broad applicability to vertebrate species. In particular, owing to their stereotyped and class-specific dendrite branching patterns, the Drosophila dendritic arborization (da) sensory neurons have emerged as an excellent model system to investigate the cellular and molecular mechanisms that regulate the acquisition of distinct dendritic architectures and receptive field specification. Indeed, studies to date, have demonstrated that genetic signatures underlying class-specific dendrite morphogenesis, are regulated by complex molecular programs acting at both the transcriptional and post-transcriptional levels. 
 Previous studies on transcription control of neuronal shape have characterized several transcription factors that function to specify and control dendritic growth/branching and cytoskeletal rearrangements. For example, members of the Cut/Cux1/Cux2 family of homeodomain transcription factors have been shown to be multi-level regulators of synaptogenesis and dendritic spine morphology in the brain cortex. While the significance of Cut in generating neuronal diversity is recognized, the machinery underlying Cut-mediated regulation of dendritic elaboration in da neurons remains largely unknown. In this study, we show evidence for dynamic links between transcriptional cues and two important conserved cellular processes that allow translation into changes in neuronal architecture: (1) Regulation of the actin and microtubule cytoskeleton and (2) The intracellular membrane transport system. Here, we implicate the Rho-GEF Trio, an evolutionarily conserved multi-functional domain protein, as an important downstream effector in Cut mediated regulation of filopodia formation, via interactions with Rac1 and Rho1. In addition, we demonstrate gene expression cascades initiated by Cut, via CrebA, that regulate a specific sub-cellular function, COPII transport, as one important means of mediating large-scale changes in cellular morphology. 
 A second crucial level of regulation lies at the post-transcriptional level in which miRNAs have emerged as very important modulation of gene expression across numerous cellular contexts, such as embryonic development, stem cell division and cancer to name a few. Several recent studies in Drosophila have implicated individual miRNAs, as well as, RISC components, essential for miRNA biogenesis, in various aspects of neuronal development including, local translation at synapses to regulate synaptic strength, and growth of dendritic spines. Despite these advances, the precise role of miRNAs in neuronal morphogenesis and, in particular, dendrite development remains largely unknown. 
 Here, we have conducted the first miRnome level investigation into the role of miRNA mediated regulation of dendrite morphogenesis using a combination of functional genomics, bioinformatics and rigorous phenotypic validation. Whole genome miRNA profiling experiments in distinct subclasses of da neurons reveal a largely differential pattern of expression for miRNAs in neurons of varying dendritic complexity. In addition, via a systematic large-scale gain-of-function screen, we have uncovered miRNAs with previously unknown functions in forming dendrite architecture. Furthermore, we provide the first evidence for the role of K box miRNAs in directing class-specific dendrite development and demonstrate that they function by targeting genes that repress dendrite complexity.



Dendrite, Mirna, Morphology, Neuron, Systems Biology, Transciption