Academic journal article Genetics

Dendritic Cytoskeletal Architecture Is Modulated by Combinatorial Transcriptional Regulation in Drosophila Melanogaster

Academic journal article Genetics

Dendritic Cytoskeletal Architecture Is Modulated by Combinatorial Transcriptional Regulation in Drosophila Melanogaster

Article excerpt

NEURONS are highly polarized cells comprised of two structurally and functionally distinct processes, the axon, which relays signals to other neurons, and the dendrites, which receive signals from other neurons. Since dendrites are the primary site of synaptic input and signal integration, with dendritic size and the range of arborization patterns affecting connectivity, the regulation of dendritic growth and branching is extremely important for the establishment of functional neuronal networks (Lefebvre et al. 2015).

Genetic and molecular studies have demonstrated that the acquisition of class-specific dendrite morphologies is mediated by complex regulatory programs involving intrinsic factors and extrinsic cues (Jan and Jan 2010; Puram and Bonni 2013; Tavosanis 2014; Nanda et al. 2017). Many of these factors are part of, or activate, signaling pathways that eventually converge on the neuronal actin and microtubule (MT) cytoskeletons. These cytoskeletal elements form the scaffold around which cell shape is built, and the tracks along which intracellular components are transported (Rodriguez et al. 2003). Despite recent progress in dissecting the roles of transcription factor (TF) activity in regulating dendritic cytoskeletal architecture (Jinushi-Nakao et al 2007; Ye et al 2011; Iyer et al. 2012; Nagel et al. 2012), much remains unknown regarding the molecular mechanisms via which TFs spatio-temporally modulate cytoskeletal dynamics to direct developing and mature arbor morphologies (Santiago and Bashaw 2014). Understanding how such changes in cytoskeletal control lead to specific changes in emergent neuron shape can be facilitated by computational simulations (Samsonovich and Ascoli 2005), especially if directly and bidirectionally linked with imaging-driven, systems-level molecular investigations (Megason and Fraser 2007).

Intriguingly, two TFs, Cut (Ct) and Knot (Kn), have been shown to synergize in promoting class IV (CIV) da neuronspecific arbor morphology by each exerting distinct regulatory effects on the dendritic cytoskeleton (reviewed in Nanda et al. (2017)). Ct, a member of the evolutionarily conserved CUX family of TFs, is a homeodomain-containing molecule with functional roles in external sensory organ cell fate specification (Bodmer et al. 1987; Blochlinger et al. 1988, 1990), class-specific da neuron dendrite morphogenesis (Grueber et al. 2003a), and dendritic targeting of olfactory projection neurons (Komiyama and Luo 2007). Ct regulates dendritic diversity among da sensory neurons in an expression-leveldependent manner. Ct protein expression in da neurons is highest in class III (CIII) neurons, followed by medium and low expression levels in CIV and class II (CII) neurons, respectively, and is undetectable in class I (CI) neurons (Grueber et al. 2003a). Genetic disruption of ct leads to severe reductions in dendritic arbor complexity, particularly the formation of actin-rich structures such as short, unbranched dendrites. Conversely, ectopic misexpression of Ct in CI neurons results in supernumerary branching and the de novo formation of F-actin-rich dendritic filopodia converting typical CI dendritic morphology toward the characteristic features of CIII neurons (Grueber et al. 2003a). In mammals, Cux1/Cux2, the vertebrate homologs of Ct, also function in regulating dendritic branching, spine morphology, and synaptogenesis in the mammalian cortex revealing the Ct/Cux molecules have evolutionarily conserved roles in dendritic development and maturation (Cubelos et al. 2010; Li et al. 2010).

Similarly, the Collier/Olf1/EBF (COE) family TF Kn, which is exclusively expressed in CIV neurons, endows these neurons with an expansive and highly branched dendritic arbor by promoting MT-dependent branching and elongation. As with ct defects, loss of kn function in CIV neurons leads to significant reductions in dendritic growth and branching resulting in rudimentary arbor complexity, and conversely, ectopic misexpression of Kn in CI da neurons promotes supernumerary higher order branches coupled with excessive dendrite branch elongation (Hattori et al. …

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