The Questions of Developmental Biology

There is some reciprocity in science, and just as research on vertebrate netrin genes led to
the discovery of their C. elegans homologues, research on the nematode UNC-5 gene led to the
discovery of the gene encoding the human netrin receptor. This turns out to be a gene whose
mutation in mice causes a disease called rostral cerebellar malformation (Ackerman et al. 1997;
Leonardo et al. 1997).
Slit proteins.
Diffusible proteins can also
provide guidance by repulsion. One very
important chemorepulsive molecule is the
Slit protein. In Drosophila, the Slit protein
is secreted by the neural cells in the
midline, and it acts to prevent most neurons from
crossing the midline from either side. The growth
cones of Drosophila neurons contain the
Roundabout (Robo) protein, which is the receptor
for the Slit protein. In this way, most Drosophila
neurons are prevented from migrating across the
midline. However, the commissural neurons that
traverse the embryo from side to side find a way to
avoid this repulsion. They accomplish this task by
downregulating the Robo protein as they approach
the midline. Once they have traveled across the
middle of the embryo, they re-express this protein
and become sensitive again to the midline inhibitory
actions of Slit (Figure 13.23; Brose et al. 1999; Kidd
et al. 1999). Slit also functions in the vertebrate
nervous system to guide neuronal growth cones.
There are three Slit proteins in vertebrates, and
they are used to turn away motor neurons and
olfactory (smell) neurons (Brose et al. 1999;
Li et al. 1999). This repulsive activity may be
extremely important for the guidance of the
olfactory neurons, since they are guided to
specific regions of the telencephalon by
repulsive cues emanating from the midline of
the forebrain (Pini 1993).
Target selection
Once a neuron reaches a group of cells wherein
lie its potential targets, it is responsive to various
proteins that are produced by the target cells. In addition
to the proteins already mentioned, some target cells
produce a set of chemotactic factors collectively called
neurotrophins. These proteins include nerve growth
factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and NT-4/5.
These proteins are released from potential target tissues and work at short ranges as either
chemotactic factors or chemorepulsive factors (Paves and Saarma 1997).