Myelination drastically speeds up action potential propagation along axons, which is
fundamental for the correct function of neuronal circuits. However, axon-oligodendrocyte
interactions regulating the onset of myelin formation remain
unclear. I sought to determine how reticulospinal axons control myelination, as they
are the first myelinated in the zebrafish spinal cord. I genetically manipulated
zebrafish in order to either remove such axons from a region of the spinal cord, or to
increase their number, and characterized oligodendrocyte-lineage cells following this
axonal loss- or gain-of-function.
In kinesin-binding protein (kbp) mutants, reticulospinal hindbrain neurons start
axonogenesis but axons fail to grow along the entire spinal cord as in wildtype,
providing an axon-deficient posterior spinal cord and an intact anterior region. I
found that early stages of oligodendrocyte development, such as the specification of
oligodendrocyte precursors, their distribution and migration were not affected in the
posterior spinal cord of these mutants. However, both the proliferation and the
survival of late precursors were impaired, resulting in a significant reduction of
mature oligodendrocytes in the posterior region of mutants at the onset of
myelination. Since the anterior spinal cord of mutants is indistinguishable from
wildtype, these results demonstrate that reticulospinal axons provide a mitogenic and
a survival signal to a subset of developing OPCs, enabling their differentiation and
lineage progression.
I then found that the absence of reticulospinal axons did not affect the timing of
oligodendrocyte differentiation, which matured on time, suggesting that this follows
an intrinsic timer, as previous studies suggested. Oligodendrocytes also did not
myelinate incorrect axonal targets, but instead adapted to the reduced axonal surface
by elaborating fewer myelin sheaths. Additionally, oligodendrocytes made shorter
sheaths, and also incorrectly ensheathed neuron somas in the mutant spinal cord,
suggesting that either kbp function or a precise amount of axonal surface are required
to prevent ectopic myelination of somas and to promote the longitudinal growth of
myelin sheaths.
In wildtype animals, the two reticulospinal Mauthner axons are the very first
myelinated in the spinal cord. In animals where Notch1a function is temporarily
abrogated or hoxb1 genes are temporarily upregulated, supernumerary Mauthner
neurons are generated. I found that these extra axons are robustly myelinated, with
no impairment of myelination of adjacent axons. Surprisingly, the number of
oligodendrocytes was not altered, but I found that each individual oligodendrocyte
elaborated more myelin sheaths, whose total length was also longer than in
wildtypes. Additionally, dorsal oligodendrocytes, which normally myelinate only
small-calibre dorsal axons, readily extended processes ventrally to myelinate the
supernumerary large-calibre Mauthner axons, in addition to small-calibre axons.
These results suggest that oligodendrocytes are plastic and are not destined to
myelinate a particular type of axon, and conversely, that axonal signals that induce
myelination are similar for different axons. The long-standing observation that
oligodendrocytes tend to myelinate either few large axons or many small axons thus
reflects local interactions of oligodendrocyte processes with the nearby axons, rather
than different subtypes of oligodendrocytes specified by an intrinsic programme of
differentiation.
Collectively, this work shows that axons extensively influence both oligodendrocyte
lineage progression and oligodendrocyte myelinating potential in vivo