This paper explores the source and
function of netrin1 for the guidance of commissural axons in the spinal cord
during development. Specifically, the authors show that axonal outgrowth
towards the ventral midline is mediated through netrin1 secreted by neural
progenitors residing in the ventricular zone (VZ), rather than netrin1 produced
in the floor plate (FP). The Gli2-/-
mutant mouse strain, which depletes netrin1 from the FP but not the VZ, was
used to show that FP-derived netrin1 is not necessary for spinal axon guidance.

NF+ axons in the Gli2-/-
mutants were not affected, but ablating netrin1 expression from the VZ via Gli2-/-;netrin1lazZ/lacZ
mice resulted in aberrant axonal trajectories. Similarly, removing netrin1 from
neural progenitors (netrin1?dVZ) significantly disrupted the activity of NF+,
Robo3+, and Tag1+ axons. These experiments were crucial
in determining that netrin1 produced in the ventricular zone is essential for
guidance activity, while the floor plate does not contribute significantly to
this phenomenon. The study then characterized the properties of the netrin1 protein
itself, using immunostaining to conclude that neural progenitors deposit
netrin1 on the laminin+ pial surface, which then accumulates on
commissural axons during their growth away from the VZ. This directed growth along
a cellular surface (termed haplotaxis) is dependent on the expression of axonal
Dcc, the receptor for the netrin1 protein. Dcc mutants were unable to complete
this guided behavior, confirming the importance of this ligand-receptor pair in
precise axonal growth. Overall, this paper established the crucial role of neural
progenitors in netrin1 secretion, which acts through a contact-based mechanism to
direct axons during embryonic development.

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            I think this paper is interesting
for multiple reasons. Through detailed and well devised experiments, the authors
were able to overturn a prevailing hypothesis in Neuroscience. Their refutation
was carefully presented and executed, starting by explaining the erroneous model,
then following up with inventive experiments that suggest a new explanation for
axon guidance. The representative images shown are very impressive, and
indicate significant thought about visualization techniques for commissural
neurons, both using immunostaining as well as fluorescent-tagged transgenic
proteins. Mechanistically, the paper is also sound, as it clearly demonstrates
the necessity of Dcc-netrin1 interactions during guidance along the pial
surface. One criticism I have of the methods is that aberrant neural
trajectories were quantified in only one way: by the number of axons that grew
into the ventricular zone. However, there are many other criteria in which axon
trajectories could be quantified, such as the overall direction of growth or the
length of misguided axons. Performing these additional quantifications in
mutant animals could provide valuable information on the results of netrin1
depletion, and characterize the phenotype of axons which have no exposure to
haplotaxis. Another aspect I would have liked to see in the paper is a study of
netrin1 function over a time course. These experiments were conducted at one
general stage of embryonic development, during which the neural progenitors
played a dominant role in haplotactic guidance mechanisms. Therefore, it would
be interesting to see if floor plate-derived netrin1 has an essential function
at time points other than the ones explicitly studied in this paper. By
experimentally manipulating the source of axon guidance molecules at different
times, a more comprehensive picture of the molecular and cellular processes
that drive neuronal development can be achieved.


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