NEURAL DEVELOPMENT IN DROSOPHILA 
YuH Nunc Jan, Ph.D., Investigator 
Dr. Jan and his colleagues are interested in the 
mechanisms of cell determination and differentia- 
tion. How is a nervous system organized during de- 
velopment? How do neurons arise from undifferen- 
tiated ectodermal cells? What gives the neurons 
their individual identities in terms of shape and 
function? How are neuronal pathways initially es- 
tablished? The long-term goal is to understand 
these processes at the molecular level. A genetic ap- 
proach is being used; i.e., first, mutants are isolated 
that affect neurogenesis, neuronal type, or axonal 
pathway formation. Identification of the mutations 
can lead to the isolation of genes important in neu- 
ronal development. 
A suitable preparation for cellular analysis of 
neural development in mutant and wild-type ani- 
mals is needed to undertake a thorough genetic 
and molecular approach. The embryonic sensory 
nervous system provided an excellent assay system. 
This system has been characterized in detail. The 
position, identity, and likely function for each indi- 
vidual cell are now known. More recently, Dr. Rolf 
Bodmer worked out much of the DNA replication 
patterns and cell lineages of this peripheral sensory 
nervous system by using the thymidine analogue 
BrdU. This has provided the groundwork necessary 
for the isolation and analysis of mutants. 
During the last few years. Dr. Jan's laboratory has 
been engaged in an extensive search for mutants af- 
fecting neural development in Drosophila. More 
than half of the genome has been screened, and 
more than 20 genes that are involved in early neu- 
ral development have been found. Mutations or de- 
letions of these genes lead to one of the following 
phenotypes: 1) severe hypertrophy or hypotrophy 
of the nervous system, 2) deletion or duplication of 
specific subgroups of neurons, 3) transformation of 
one neuronal type into another, or 4) misrouting of 
the axonal pathway. 
Several of these mutants are likely to play key 
roles in the development of the embryonic sensory 
nervous system. These genes are being analyzed at 
the molecular level. 
I. Genes Required for the Formation of Sensory 
Organ Precursors. 
An undifferentiated ectodermal cell can become 
either an epidermal cell or a sensory organ precur- 
sor. Dr. Jan and his colleagues found a gene, 
daughterless (da), that plays a crucial role in deter- 
mining whether a cell becomes a sensory organ 
precursor. Deletion of da was known previously for 
its role in sex determination, as studied by Dr. 
Thomas Cline at Princeton University In Drosoph- 
ila, sex is determined by the ratio of the number of 
X chromosomes to the number of autosomes. The 
gene Sex lethal (Sxl) seems to play a central role. If 
Sxl is on, it turns on downstream genes, such as tra 
and tra-2, resulting in female development, da is a 
positive regulator of Sxl; the da gene product is 
supplied by the mother and is required early during 
embryogenesis to turn on Sxl. If the maternal sup- 
ply of the da gene product is greatly reduced or ab- 
sent, Sxl is off This does not affect male develop- 
ment, because Sxl is normally off in male embryos. 
However, in female progeny of da mutant female 
flies, the lack of Sxl function causes abnormal dos- 
age compensation and, as a result, lethality This ex- 
plains the "daughterless" phenotype. da is required 
not only for sex determination but also for neu- 
rogenesis. This is an example of two seemingly un- 
related biological processes that are involved in the 
function of a particular gene. 
Recently, Drs. Michael Gaudy and Harald Vaessin 
have cloned da. The sequence of the transcripts 
predicts a protein product of 710 amino acids. It 
shares significant sequence similarities with a num- 
ber of genes [the nuclear oncogene myc; the Dro- 
sophila achaete-scute complex (AS-Q, which is 
known to be involved in neuronal determination; 
and MyoDl, which can transform fibroblasts into 
myoblasts]. Moreover, the region of sequence simi- 
larity (the myc-similarity region) has been shown to 
be both necessary and sufficient for the myoblast- 
transforming ability ot MyoDl . Thus there is grow- 
ing evidence that this myc-similarity region is an im- 
portant functional motif shared by many genes 
involved in specifying cell fate. 
More recently, a striking similarity has been 
found between da and a human immunoglobulin 
enhancer-binding protein (75% identity over 85 
amino acids of the mjc-similarity region and the ad- 
jacent L repeat). This conserved region contains the 
DNA-binding activity of the enhancer-binding pro- 
tein. By analogy, most likely da also functions as a 
DNA-binding transcription regulator. 
How might da function in such different pro- 
cesses as neuronal development and sex determina- 
tion? One hypothesis is that the same da protein, 
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