发信人: Morphin (莫非你是飞鸟；我养鱼), 信区: Biology
标 题: SHH: A Morphogen and Axonal Guidance Cue
发信站: The unknown SPACE (Sat Apr 19 12:57:18 2003) WWW-POST

MCBJC Discussion for the week of 4/21

Sonic Hedgehog: A Morphogen and Axonal Guidance Cue

Hedgehog is probably the most well-known morphogen in embryo development. As a
multifunctional molecule involved in cell differentiation, cell proliferation
and tissue patterning, hedgehog's functions as a morphogen have been
extensively studied. However, recent studies about another morphogen - BMP
family revealed its involvement in repelling spinal cord commissural axons.
Thus the possibility that Sonic Hedgehog (SHH), a vertebrate Hedgehog may
attract commissural axons toward the ventral midline of spinal cord has been
explored in the following paper:

The Morphogen Sonic Hedgehog is a Axonal Chemoattractant that Collaborates
with Netrin-1 in Midline Axon Guidance

Frederic Charron et al.

Cell Vol 113, 11-23, April 4, 2003

The background information about axon guidance was generally reviewed in
Tessier-Lvigne and Goodman, Science 274, 1123-1133. The floor plate cells
located in the ventral midline of spinal cord have a potent attractive
activity to the commissural axons originated from the commissural interneurons
located in the dorsal spinal cord. Previous studies have attributed this
chemoattractant activity mainly to Netrin-1, but also suggested the existence
of additional chemoattractant molecules in the floor plat cells.
Given the expression of SHH in the floor plate, SHH is thought a candidate
chemoattractant. In fact it has been shown in the above paper that SHH have
this chemoattractant activity in vitro by explants and Xenopus axon turning
assay and that SHH signaling is required for the correct axon projection of
pinal cord axons in vivo by conditional knock-out of Smo, a receptor component
for SHH signaling. One interesting characteristics shared by morphogens and
axon guidance cues is that they probably function thru a long range gradient.
Therefore, it is quite intriguing to see these molecules have been reused for
different purposes thru the evolution.

The floor plate is a good system to study axon guidance in the spinal cord, as
mentioned in the above paper. However, there are still many questions
remaining about the commissural axon guidance, probably due to the
over-complexity of in vivo system: redundancy and variety of guidance cues
existed in the floor plate. Here are a couple of questions for our discussion:

1) Fig 1 shows the axon guidance phenotype in gli2 and/or net-1 mutants. Can
you provide an explanation for gli2 mutant, which lacks the floor plate
(certainly no net-1 expression in the floor plate)but has a less severe
phenotype (more commissural axons reach the floor plate), compared to net-1
-/- and gli2 net-1 double mutant?

2) Fig 2 shows SHH can alter the axon projection in spinal cord explants in
the absence of Net-1, but Fig 4 shows SHH itself can't elicit axon growth
without Net-1 and even can't attract axon when Net-1 protein is supplemented
in the medium(Fig 4g). How to explain this result?

3) Netrin-1 has been postulated to allow commissural axons to grow into the
non-permissive zone in the ventral spinal cord in this paper and they
interpreted that the residue net-1 expression in the ventricular zone overcome
the non-permissive environment of the ventral spinal cord and hence more
commissural axons in that region in gli2 -/-. Do you think there is another
implication from this explanation?



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