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WIREs Dev Biol
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A fly's view of neuronal remodeling

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Developmental neuronal remodeling is a crucial step in sculpting the final and mature brain connectivity in both vertebrates and invertebrates. Remodeling includes degenerative events, such as neurite pruning, that may be followed by regeneration to form novel connections during normal development. Drosophila provides an excellent model to study both steps of remodeling since its nervous system undergoes massive and stereotypic remodeling during metamorphosis. Although pruning has been widely studied, our knowledge of the molecular and cellular mechanisms is far from complete. Our understanding of the processes underlying regrowth is even more fragmentary. In this review, we discuss recent progress by focusing on three groups of neurons that undergo stereotypic pruning and regrowth during metamorphosis, the mushroom body γ neurons, the dendritic arborization neurons and the crustacean cardioactive peptide peptidergic neurons. By comparing and contrasting the mechanisms involved in remodeling of these three neuronal types, we highlight the common themes and differences as well as raise key questions for future investigation in the field. WIREs Dev Biol 2016, 5:618–635. doi: 10.1002/wdev.241 This article is categorized under: Nervous System Development > Flies
Mushroom body (MB) γ neurons undergo stereotypic remodeling: at larval stage, MB γ neurons project a single axon that branches to form dendrites (den), a tightly fasciculated axon peduncle (p) that bifurcates to form the dorsal (d) and medial (m) lobes. Cortex glia (yellow) instruct MB axon pruning by secreting the TGF‐β ligand Myoglianin. At 6 h after puparium formation (APF), MB γ dendrites are mostly eliminated and axons begin to undergo defasciculation, allowing the astrocytes (green) to infiltrate the dorsal and medial lobes. The role of the remaining unidentified glia or cortex glia during this and later time points is not known (gray). At 12 h APF, axon fragmentation and blebbing are apparent. At 18 h APF, fragmentation is complete and axonal fragments are being engulfed mainly by astrocytes. At 24 h APF, the MB γ neurons begin to regrow toward the adult targets, forming the adult γ lobe. [Reprinted with permission from Ref . Copyright 2014]
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Regrowth in MB γ and CCAP neurons requires TOR signaling: in the MB, nitric oxide synthase (NOS) inhibits the formation of a stable E75/UNF complex. Under low nitric oxide conditions, the nuclear receptors E75 and UNF function together to induces regrowth via the TOR and S6K pathway. In CCAP neurons, unknown signals inhibit the transcription factor FOXO and activate the transcription factors Cabut (Cbt). The downregulation of FOXO allows derepression of the insulin/TOR pathway, which, in turn, induces regrowth. Cbt functions via an unknown mechanism. Green indicates common factors in both systems.
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Degradation pathways inducing da dendrite and MB γ neurons pruning: in da neurons, Uba1, the sole Drosophila E1, activates the E2 UbcD1, which then activates the E3 ligase DIAP‐1 and causes it to undergo self‐promoting degradation. The degradation of DIAP‐1 disinhibits the expression of the caspase Dronc and allows the subsequent elevation of caspase activity, which in turn promotes dendrite pruning by unknown mechanisms. At the same time a Cullin1 (Cul1)‐based E3 complex is activated by an unknown E2 and promotes pruning by inhibiting the insulin pathway. In addition, Valosin‐containing protein, a ubiquitin sensitive chaperone, promotes the degradation of DIAP‐1 and in parallel allows for the correct splicing of mical mRNA. In the MB, Uba1 is required to for axon pruning but the relevant E2 complexes are largely unknown. The Cul1‐based SCF E3 ligase complex promotes axon pruning in the MB by an unknown mechanism. Green indicates common factors in both systems and red are targets that were tested and found not to be involved.
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Mechanisms of ecdysone receptor B1 (EcR‐B1) signaling to trigger pruning in MB γ and da neurons. In da neurons, EcR‐B1 triggers dendrite pruning via Sox‐14 and Hdc. Sox‐14 promotes pruning via Mical and Cullin1‐based SCF E3 ligase (see text for more information). In MB neurons cortex, and perhaps also astrocyte‐like, glia secrete Myoglianin (Myo) a TGF‐β ligand that binds to neuronal TGF‐β receptors that induce the expression of EcR‐B1 in MB γ neurons. Cell autonomous functions of Cohesin and Ftz‐F1 include the activation of EcR‐B1. EcR‐B1 activates Sox‐14, which functions in a non‐Mical dependent pathway, and probably other pathways, to induce pruning. Green indicates common factors in both systems and red are targets that were tested and found not to be involved.
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Remodeling of MB γ neurons, da dendrites and CCAP neurons occur on similar time scales. Pruning (orange) of MB γ axons, da dendrites, and CCAP neurites all begin close to pupation onset and ends by 20 h APF. Regrowth (green) begins around 24 h APF and lasts between 24 and 48 h.
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Remodeling of CCAP/Bursicon neurons during metamorphosis: in the larval and prepupal stage, CCAP expressing neurons line the entire ventral nerve cord (VNC) and form an intricate network. There are two major types of neurons, efferent neurons, and interneurons. Efferent neurons (one example highlighted in red) send projections from the cell bodies, that are located on both sides of the VNC, cross to the midline where they then exit the VNC through the dorsal part of the VNC. The neurites of the interneurons (one example highlighted in blue) cross the midline and then bifurcate to send projections to both the anterior and posterior areas of contralateral side of the VNC. At 6 h APF pruning begins with the neurites in the center of the VNC disappearing first followed by the longitudinal tracts. At the onset of regrowth (36 APF), cell somas are also beginning to migrate to the abdominal area of the VNC. At the adult stage, cell somas are up to twice the size of larval somas and they send projections through the adult VNC. By 60 h APF, the CCAP neurons have acquired their final adult connectivity with the unipolar neurons sending their dendrites up along the VNC while their axons enter the VNC at the midline and exit from the ventral side of the VNC to innervate their targets. Labels are major time occurances of processes. For more detailed time analysis, see Figure (based on Refs and ).
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Dendrite remodeling of da class IV during metamorphosis: at the white prepupal stage (0 h APF), da class IV neurons extend a complex dendritic arbor (green) as well as a single axon projecting ventrally to the ventral nerve cord (purple). Dendrites undergo blebbing, thinning, and proximal severing at about 5 h APF, followed by fragmentation (12 h APF). By 16–18 h APF, all dendrites have been fragmented and debris are engulfed and degraded largely by epidermal cells (background open brown silhouettes) but also by phagocytic hemocytes (brown). At 24 h APF, the dendrite begins to regrow by extending primary branches. By 72 h APF, the entire elaborate dendritic tree has regrown. Arrows point to areas of proximal severing of the dorsal dendrite branches or of dendrite thinning.
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