Neural Development in Drosophila 
Yuh Nungjan, Ph.D. — Investigator 
Dr. Jan is also Professor of Physiology and Biochemistry at the University of California, San Francisco. 
Although Dr. Jan went to the California Institute of Technology to study theoretical physics, he instead 
became interested in biology and received his Ph.D. degree from Caltech in biophysics and physics. While 
there he studied sensory transduction of the fungus Phycomyces with Max Delbriick. Dr. Jan began his 
study of the nervous system during postdoctoral research with Seymour Benzer at CalTech and continued 
this line of research with Stephen Kuffler at Harvard Medical School. His primary interest remains the 
nervous system. 
HOW a nervous system is organized during 
development is a major unresolved problem 
in biology. For several years our laboratory has 
been interested in the following questions: How 
do neurons arise from undifferentiated ectoder- 
mal cells? What gives the neurons their individual 
identity in terms of shape and function? 
Our long-term goal is to understand these pro- 
cesses at the molecular level, and our approach is 
a genetic one. We first isolate mutations that af- 
fect neurogenesis, neuronal type, or axonal path- 
way formation. Identification of these mutations 
can lead to the isolation of important genes. 
During the last few years, our laboratory has 
been engaged in an extensive search and analysis 
of mutants affecting neural development in the 
fruit fly Drosophila. To identify and analyze such 
mutants, we have been using the embryonic sen- 
sory nervous system, which has been character- 
ized in considerable detail at the single-cell level. 
Roughly half of the Drosophila genome has been 
screened for mutations that alter the peripheral 
nervous system (PNS), resulting in the identifica- 
tion of a number of genes that specify cell fate in 
the embryo. Analysis of those genes had led us to 
propose a "progressive determination of the 
PNS" model. 
Early during embryogenesis, cells in different 
locations within the ectodermal layer acquire un- 
equal developmental potential as a result of the 
actions of the "prepattern genes." These include 
genes that specify dorsoventral and anteroposte- 
rior orientation as well as segmentation. Cells 
from some of the domains are affected by the ac- 
tion of "proneural" genes, which apparently en- 
dow cells with the competence to become neuro- 
nal precursors. Genes of the achaete scute 
complex {AS-C) and daughterless {da) belong 
to this group. Both y45-C and da encode proteins 
with the helix-loop-helix motif. It is likely that 
products of these genes may form homo- or heter- 
odimers that bind to DNA and regulate the tran- 
scription of target genes in order to initiate neuro- 
nal precursor development. 
As a neuronal precursor forms, it inhibits neigh- 
boring cells from doing so. This "lateral inhibi- 
tion" involves the action of six known "neuro- 
genic" genes. Removing the function of any of 
the six. Notch, Delta (Dl), the Enhancer of split 
complex [E(spl)-C\, mastermind (mam), neu- 
ralized (neu), and big brain {bib), leads to hy- 
pertrophy of both the central nervous system 
(CNS) and the PNS, presumably as a result of los- 
ing lateral inhibition. 
There appear to be at least two independent 
cell-cell interaction pathways. One is mediated 
by the gene products of Notch and Dl, both cod- 
ing for membrane proteins with epidermal 
growth factor (EGF)-Iike repeats. E(spl)-C, 
mam, and perhaps neu are involved in this path- 
way. The second pathway is mediated by bib, 
which encodes a membrane protein with signifi- 
cant homology to the bovine major intrinsic pro- 
tein (MIP), soybean nodulin 26, and Escherichia 
coli glycerol facilitator, which allows passive 
transport of small molecules such as glycine. 
The commitment of neuronal precursors may 
involve the actions of a group of "master regula- 
tory" genes, which endow the precursor with 
certain unique properties of the nervous system. 
The identity of a neuronal precursor is further 
specified by "neuronal-type selector" genes. For 
example, the cut locus is required for external 
sensory organs to acquire their correct identity. 
In the absence of cut function, these organs are 
transformed into chordotonal organs. Normally 
cut is expressed in sensory organ precursors but 
not in chordotonal organ precursors, and we 
think that the cut gene determines which organ 
the precursor will develop into. The cm? product 
contains a homeodomain and is likely to act as a 
transcription factor regulating the expression of 
downstream differentiation genes. 
Recently we began to work on the problem of 
axonal pathfinding and target recognition in Dro- 
sophila. Tracing the axonal pathway in the fly 
nervous system had been problematic in the past. 
Because of the small size of the neurons, it was 
difficult to use traditional methods to trace path- 
ways, such as filling neurons with fluorescent 
dyes and other tracers. However, Ed Giniger, a 
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