The Questions of Developmental Biology

The complicated nerve fiber circuits of the brain grow, assemble, and organize themselves
through the use of intricate chemical codes under genetic control. Early in development, the
nerve cells, numbering in the millions, acquire and retain thereafter, individual identification
tags, chemical in nature, by which they can be distinguished and recognized from one another.
Current theories do not propose a point-for-point specificity between each axon and the
nerve that it contacts. Rather, evidence now demonstrates that gradients of adhesivity (especially
those involving repulsion) play a role in defining the territories that the axons enter, and that
activity-driven competition between these neurons determines the final connection of each axon.
Adhesive specificities in different regions of the tectum.
There is good evidence that retinal ganglion cells can distinguish between regions of the
tectum. Cells taken from the ventral half of the chick neural retina preferentially adhere to dorsal
halves of the tectum, and vice versa (Roth and Marchase 1976; Gottlieb et al. 1976; Halfter et al.
1981).
Retinal ganglion cells are specified along the dorsal-ventral axis by a gradient of
transcription factors. Dorsal retina are characterized by high concentrations of the Tbx5
transcription factor, while ventral retinal cells have high levels of Pax2. These transcription
factors are induced by paracrine factors (BMP4 and retinoic acid, respectively) from nearby
tissues (Koshiba-Takeuchi et al. 2000). Misexpression of Tbx in the early chick retina results in
marked abnormalities of the retinal-tectal projection. Therefore, the retinal ganglial cells are
specified according to this location.
One gradient that has been identified functionally is a gradient of repulsion that is highest
in the posterior tectum and weakest in the anterior tectum. Bonhoeffer and colleagues (Walter et
al. 1987; Baier and Bonhoeffer 1992) prepared a "carpet" of tectal membranes having alternating
stripes derived from the posterior and the anterior tecta. They then let cells from the nasal
(anterior) or temporal (posterior) regions of the retina extend axons into this carpet. The ganglion
cells from the nasal portion of the retina extended axons equally well on both the anterior and
posterior tectal membranes.
The neurons from the temporal
side of the retina, however, extended
axons only on the anterior tectal
membranes (Figure 13.30). When the
growth cone of a temporal retinal
ganglion axon contacted a posterior
tectal cell membrane, the filopodia of
the growth cone withdrew, and the
growth cone collapsed and retracted
(Cox et al. 1990).
The basis for this specificity appears to be gradients of ephrin proteins and their
receptors. In the optic tectum, ephrin proteins (especially ephrins A2 and A5) are found in
gradients that are highest at the posterior (caudal) of the tectum and decline anteriorly (rostrally)
(Figure 13.29A). Moreover, cloned ephrin proteins have the ability to repulse axons (Figure
13.29B), and ectopically expressed ephrin will prohibit axons from the temporal (but not from the
nasal) regions of the retina from projecting to where it is expressed (Drescher et al. 1995;
Nakamoto et al. 1996).