Dynamics of degeneration and regeneration in developing zebrafish peripheral axons reveals a requirement for extrinsic cell types.
BACKGROUND
Understanding the cellular mechanisms regulating axon degeneration and regeneration is crucial for developing treatments for nerve injury and neurodegenerative disease. In neurons, axon degeneration is distinct from cell body death and often precedes or is associated with the onset of disease symptoms. In the peripheral nervous system of both vertebrates and invertebrates, after degeneration of detached fragments, axons can often regenerate to restore function. Many studies of axonal degeneration and regeneration have used in vitro approaches, but the influence of extrinsic cell types on these processes can only be fully addressed in live animals. Because of its simplicity and superficial location, the larval zebrafish posterior lateral line (pLL) nerve is an ideal model system for live studies of axon degeneration and regeneration.


RESULTS
We used laser axotomy and time-lapse imaging of pLL axons to characterize the roles of leukocytes, Schwann cells and target sensory hair cells in axon degeneration and regeneration in vivo. Immune cells were essential for efficient removal of axonal debris after axotomy. Schwann cells were required for proper fasciculation and pathfinding of regenerating axons to their target cells. Intact target hair cells were not themselves required for regeneration, but chemical ablation of neuromasts caused axons to transiently deviate from their normal paths.


CONCLUSIONS
Macrophages, Schwann cells, and target sensory organs are required for distinct aspects of pLL axon degeneration or regeneration in the zebrafish larva. Our work introduces a powerful vertebrate model for analyzing axonal degeneration and regeneration in the living animal and elucidating the role of extrinsic cell types in these processes.
FONDAP Center for Genome Regulation, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Santiago, Chile.
Rosario
R
Villegas
Seanna M
SM
Martin
Kelley C
KC
O'Donnell
Simon A
SA
Carrillo
Alvaro
A
Sagasti
Miguel L
ML
Allende
D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000502:physiology*; D019771:Axotomy; D003300:Copper / Q000494:pharmacology / Q000627:therapeutic use; D004625:Embryo, Nonmammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009416:Nerve Regeneration / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010525:Peripheral Nerves / Q000166:cytology* / Q000196:embryology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D012583:Schwann Cells / Q000166:cytology / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D020032:Tyrphostins / Q000494:pharmacology / Q000627:therapeutic use; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
D003300:Copper; D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D015534:Trans-Activators; D014157:Transcription Factors; D020032:Tyrphostins; D029961:Zebrafish Proteins; D000099232:Proto-Oncogene Protein Spi-1; C514187:Atoh1a protein, zebrafish; C101044:RTKI cpd