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 Delbrtick. 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 the last few years, we have been 
interested in the following questions in neural 
development: How do neurons arise from undif- 
ferentiated ectodermal cells? What gives them 
their individual identity as to shape and function? 
Our long-term goal is to understand these pro- 
cesses at the molecular level. Our approach, es- 
sentially genetic, is first to isolate mutations that 
affect neurogenesis, neuronal type, or axonal 
pathway formation, and then to identify these 
mutations, leading to the isolation of important 
genes. 
During the last five years, our laboratory has 
been engaged in an extensive search and analysis 
of mutants affecting neural development in Dro- 
sophila. To identify and analyze such mutants, 
we are using the embryonic sensory nervous sys- 
tem, which has been characterized in consider- 
able detail at the single-cell level. Roughly half of 
the Drosophila genome has been screened for 
mutations that alter the peripheral nervous sys- 
tem (PNS) . This has resulted in the identification 
of a number of genes that specify cell fate in the 
embryonic fly. Analysis of those genes led us to 
propose a model for "progressive determination 
of the PNS." 
Early during embryogenesis, cells in different 
locations within the ectodermal layer acquire un- 
equal developmental potential, as a result of 
genes that specify positions in the embryo, the 
"prepattem genes." These include, genes that 
specify dorsal-ventral and anterior-posterior 
axes. Some cells apparently acquire the potential 
to become neuronal precursors from the action of 
"proneural genes," which include, for example, 
genes of the achaete-scute complex {AS-C) and 
daughterless (da). Both AS-C and da encode 
proteins with the helix-loop-helix (HLH) struc- 
tural motif. It is likely that AS-C and da products 
form homo- or heterodimers that bind to DNA and 
regulate the transcription of target genes, initiat- 
ing neuronal precursor development. 
As a neuronal precursor forms, it inhibits neigh- 
boring cells from assuming this role. Such "lat- 
eral inhibition" involves the action of "neuro- 
genic genes." Removing the function of any of 
the six known zygotic neurogenic genes — Notch 
(IV), Delta (Dl), the Enhancer of split complex 
[E(spl)-C\, mastermind (mam), neuralized 
(neu), and big brain (bib) — leads to hyper- 
trophy of both the central nervous system (CNS) 
and the PNS, presumably as a result of losing lat- 
eral inhibition. 
There appear to be at least two independent 
cell-cell interaction pathways. One is mediated 
by the gene products of A'^and Dl, both encoding 
for membrane proteins with epidermal growth 
factor (EGF)-like repeats. E(spl)-C, mam, and 
perhaps neu are involved. The second pathway is 
mediated by bib, which encodes a membrane 
protein with significant homology to the bovine 
major intrinsic protein (MIP), soybean nodulin 
26, and E. co// glycerol facilitator, which allows 
passive transport of small molecules such as gly- 
cine. The commitment of neuronal precursors 
may involve the actions of certain "master regula- 
tory genes," which lock a cell into a particular 
fate. 
The identity of a neuronal precursor is further 
specified by "neuronal type selector genes." 
These control the type of sensory neuron that a 
precursor will give rise to. For example, the cut 
locus is required for external sensory organs to 
acquire their correct identity. In the absence of 
cut function, those organs are transformed into 
chordotonal organs. Normally cut is expressed in 
external sensory organ precursors but not in 
chordotonal organ precursors. We think that ex- 
pression of CM? gene activity determines which of 
the two types of organs the precursor will be- 
come. The CM? product contains a homeodomain 
and probably acts as a transcription factor regu- 
lating the expression of downstream differentia- 
tion genes. 
Sequence information on a number of genes 
involved in neural development indicates that 
the majority of these genes contain a previously 
identified functional motif — e.g., the EGF repeat 
in Notch, the tyrosine kinase domain in seven- 
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