Growth Cone Guidance and Neuronal 
Recognition in Drosophila 
Corey S. Goodman, Ph.D. — Investigator 
Dr. Goodman is also Class of '33 Professor of Neurobiology and Genetics in the Department of Molecular 
and Cell Biology at the University of California, Berkeley, and Adjunct Professor in the Department of 
Physiology at the University of California, San Francisco. He received his B.S. degree in biology from 
Stanford University and his Ph.D. degree in developmental neurobiology from the University of California, 
Berkeley. His postdoctoral work in developmental neurobiology was done at the University of California, 
San Diego. Prior to his present position, Dr. Goodman was a faculty member at Stanford University. His 
honors include the Alan T. Waterman Award from the National Science Board. 
WE are interested in understanding the mo- 
lecular mechanisms by which neuronal 
growth cones find their way toward, and ulti- 
mately recognize, their correct targets during de- 
velopment. Growth cones navigate over long dis- 
tances and often through a series of complex 
choice points, appearing to follow signals on the 
surfaces of cells and in the extracellular environ- 
ment. Our studies are aimed at uncovering the 
molecules and mechanisms that impart specific- 
ity to the developing nervous system and thus al- 
low growth cones to recognize their correct path- 
ways and targets. To address these issues, we use 
molecular genetic approaches in the fruit fly 
Drosophila. 
Guidance of Pioneers 
Within and just outside of the developing cen- 
tral nervous system (CNS) , certain glial cells and 
other special midline cells provide instructive in- 
formation for the differential guidance of the ini- 
tial, "pioneering" growth cones as they choose 
which cells to extend toward or along. For exam- 
ple, a specific subset of cells at the midline ap- 
pears to provide an attractive cue for the growth 
cones that extend toward the midline and pio- 
neer the commissural axon pathways that con- 
nect the two sides of the developing CNS. Simi- 
larly, a specific pattern of longitudinal glia 
appears to provide an important substrate for the 
formation of the longitudinal axon tracts that 
connect adjoining segments of the CNS. We have 
conducted a large-scale screen for mutations that 
perturb the guidance of pioneering growth 
cones. 
Of the hundreds of new mutations identified in 
this screen, mutations in three genes are of partic- 
ular current interest. Mutations in longitudinals 
lacking (fold) have a dramatic phenotype. al- 
though both commissural and peripheral path- 
ways are normal, as are most other aspects of em- 
bryogenesis, the CNS of these mutants lack all 
longitudinal axon tracts. In lola mutant embryos, 
the longitudinal glia are born, initially migrate, 
and divide as normal; the earliest defect is seen 
about the time that the first growth cones contact 
these glia and fail to extend along them. 
Mutations in the second gene, commissure- 
less, have an equally dramatic phenotype: al- 
though all other axon pathways are normal, the 
CNS of these mutants lack all commissural path- 
ways. They also have normal peripheral nervous 
system (PNS) axon pathways, muscles, sensory 
organs, and body organization. In these mutant 
embryos, the growth cones of CNS neurons do not 
extend across the midline and commissures never 
form, although other aspects of embryonic pat- 
tern formation and neuronal development appear 
normal. The commissureless gene product is a 
good candidate to be either the signal or the re- 
ceptor for the guidance of growth cones toward 
the midline. 
Mutations in a third gene, roundabout (robo) , 
lead to a dramatic misrouting of the growth cones 
that normally pioneer the MPl pathway. For ex- 
ample, the MPl growth cone extends across the 
anterior commissure where it contacts its homo- 
logue from the other side, rather than proceeding 
posteriorly. In contrast, many other longitudinal 
pathways develop as normal in robo mutant 
embryos. 
Pathway Recognition 
Once the initial axon pathways are established, 
the predominant guide for "follower" growth 
cones is the surface of the earlier axons in these 
pathways. Growth cones are able to distinguish 
one particular axon bundle, or fascicle, out of an 
array of many. The experimental analysis of these 
phenomena led to the labeled pathways hypothe- 
sis, which holds that axon pathways are diff'eren- 
tially labeled by recognition molecules that en- 
able growth cones to navigate through complex 
choice points. To identify such recognition mole- 
cules, we used an immunological approach to 
identify and subsequently clone the genes encod- 
ing five diff'erent surface glycoproteins: fasciclin 
I, fasciclin II, fasciclin III, fasciclin IV, and neuro- 
glian (a sixth, connectin, has recently been 
cloned using a different method, as described in 
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