Light stimuli perceived in the retina are transmitted
to relay neurons, the retinal ganglion cells. In mammals,
axons of these cells exit from both eyes and converge
at the midline of the ventral diencephalon to form the
optic chiasm, then project to visual centers in the
thalamus and superior colliculus and, from there, to
the cerebral cortex. Unlike non-mammalian vertebrates,
which have retinal projections to the contralateral
side of the brain, in animals with more frontally located
eyes some axons do not cross the midline and instead
project to the ipsilateral visual centers. This partial
decussation allows input from temporal axons of the
ipsilateral eye and nasal axons of the contralateral
eye, which perceive the same visual hemifield, to converge
at higher visual centers, thereby supporting binocular
vision and depth perception. In mice, Dr. Mason's model
animal, only about 3 percent of RGC axons project ipsilaterally,
whereas in humans, nearly 50 percent of axons project
ipsilaterally.
Dr. Mason's lecture reviewed her laboratory's analyses
over the last two decades designed to study how the
optic chiasrn is established. They focused on the growing
tips of the axons of retinal ganglion cells and chronicled
the behaviors of growth cones as they cross, or avoid,
the optic chiasm midline to form the binocular projections,
a process that occurs in the third gestational week
in the mouse. They also characterized the cellular ensembles
at the optic chiasm midline. Dr. Mason hypothesized
that these specialized glia and neurons express regulatory
genes and guidance factors that cordon axons into tracts,
specify where the X-shaped chiasm should form, and direct
passage of retinal axons across or away from the midline.
More recently, she has identified programs of gene
expression and guidance receptor expression for the
uncrossed retinal projection. EphBl receptor is expressed
exclusively in the ventrotemporal retinal ganglion cells
(RGCs) and is important for interacting with the ligand
ephfln-B2 in the midline glia, to cause repulsion away
from the midline. The transcription factor Zic2 is expressed
similarly in the retina and, like EphBi, is essential
for the formation of the uncrossed program. Dr. Mason
was able to determine that Nr-CAM, a member of the Li
family of cell adhesion molecules, is required for the
act of crossing the midline, especially for a late-born
population of retinal ganglion cells from ventrotemporal
retina. Such definition of molecular expression in sectors
of the retina assigns cell identity and fate with regard
to laterality of projection. The study of the retina-optic
chiasm pathway not only informs on how the binocular
pathways are established, but helps to categorize programs
of gene expression for formation of circuits, a current
major effort in neuroscience.
New work in Dr. Mason's laboratory seeks to identify:
1) whether the transcriptional regulators that were
identified, such as Zic2, directly regulate the expression
of guidance receptors such as EphBl; 2) whether the
protein for such receptors is locally translated as
growth {±nes enter the midline and interact with ephrin-B2-laden
radial glia; and 3) the signaling pathways during receptorligand
interactions.
An offshoot of this work pertains to the human condition,
in the genetic model of the albino mammal. Many genes
can cause albinism, most of which are important for
melanin synthesis or melanin granule packaging turnover.
For as yet unknown reasons, the reduction in pigment
in cells behind the retina always leads to a dimunition
in the uncrossed axonal projection, with resultant problems
in binocular vision, photophobia, and misaligned eyes.
Because the gene they identified as crucial for the
uncrossed component, Zic2, is also reduced, they will
be able to make inroads into the connection between
perturbations in melanogenesis and perturbed visual
pathways.
