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Segmentationand meotic gene fundion in tile developing
nervoussystemof Drosophila
Chris Q. Doe and M a t t h e w P. Scott
Segmentation and homeotic genes of the fruit fly
Drosophila control the pattern and identity of segments
in the embryonic and adult epidermis. Most of these
genes are also expressed in the developing nervous
system, as are related vertebrate genes. Recent evidence
suggests that segmentation genes are required for early
steps in neuronal determination, whereas homeotic
genes control segment-specific neuronal differences.
Central to the progress of Drosophila developmental
biology has been the genetic identification of segmentation and homeotic genes (reviewed in Refs 1-3).
The molecular biology of these genes, and the
phenotypes of the mutants, have led to increasingly
detailed models of cell determination in the blastoderm and epidermis. Many of the segmentation and
homeotic genes are also expressed in the Drosophila
central nervous system (CNS), and all known vertebrate homologs of these genes have also been
observed in the CNS ¢-12. In this article we review
what is currently known about the expression and
function of the segmentation and homeotic genes in
the Drosophila CNS.
Segmentation genes can be classified into three
groups: gap, pair-rule, and segment polarity, based on
the pattern of defects seen in mutant embryos 13. Gap
mutants have a deletion of a contiguous group of
segments. Pair-rule mutants have homologous
defects in alternate segments [e.g. the fushi tarazu
(flz) and even-skipped (eve) loci]. The third group, the
segment polarity genes [e.g. engrailed (en)], are
required for pattern formation within each segment.
Together, the segmentation genes interact to establish the segmental periodicity of the embryo and
control the identity of cells within each segment.
Homeotic genes, in contrast, do not affect segment
boundaries; the loss of a homeotic gene function leads
to the transformation of part or all of a segment into a
pattern characteristic of another segment. Many of
the homeotic genes are located in two clusters, the
bithorax complex (BX-C) 14 and the Antennapedia
complex (ANT-C) 15. Intensively studied homeofic
genes include Ultrabithorax (Ubx) of the BX-C, and
Antennapedia (Antp), Sex combs reduced (Scr), and
Deformed (Dfd) of the ANT-C. Segmentation and
homeofic genes together form a hierarchical network
that subdivides the embryonic epidermis into metameric units, governs determination of cells within a
segment, and establishes the distinctive pattern of
each segment.
Localization of segmentation and homeotic gene
products reveals distributions in the blastoderm, and
in epidermal cells in older embryos, that generally
correspond to the sites of function of these genes as
deduced from analysis of mutant phenotypes ~6-26.
The blastoderm-stage embryo is composed of about
TINS, Vol. 11, No. 3, 1988
6000 cells in a surface monolayer enclosing the yolk.
Each segment primordium is three to four cells wide
in the anterior-posterior axis, and forms a band
around the embryo. The pair-rule segmentation genes
are expressed in seven transverse stripes of three to
four cells width with a two-segment primordium
periodicity, while the segment polarity genes are
expressed in 14 or 15 stripes of one cell width in each
segment primordium. Correspondingly, the absence
of a pair-rule gene function leads to defects in
alternate segments, while segment polarity mutations
cause defects in part of each segment. Expression of
segmentation and homeotic genes is also observed in
many internal tissues, most strikingly in the CNS.
Before discussing the expression patterns and functions of the segmentation and homeotic genes in the
nervous system, we will review how the Drosophila
CNS is generated.
After gastrulation, the CNS develops from a single
cell layer of ventral ectoderm called the neurogenic
region 27. Between four and eight hours of development, about 20% of the neuroectodermal cells enlarge
and move into the interior of the embryo27, where
they differentiate into a stereotyped pattern of about
25 neuronal precursor cells (neuroblasts) per hemisegment 2s. Each neuroblast is a stem cell, budding off
dorsally a chain of smaller progeny called ganglion
mother cells. A ganglion mother cell then divides
once to produce two postmitotic neurons. In both
Drosophila and grasshopper, each neuroblast generates a stereotyped, characteristic family of neurones,
allowing individual neuroblasts to be identified on the
basis of the neurons they produce 28-3°. In addition,
individual neuroblasts can be identified in both fly and
grasshopper embryos by their position in the segmental pattern of neuroblasts 28'31'a2. Axonogenesis begins
between nine and ten hours of development, while
much of neuronal differentiation (e.g. initiation of
membrane excitability, synthesis of neurotransmitters and receptors) begins after 14 hours of development. The CNS of the embryo persists, with modifications, throughout the larval and pupal stages and
into adulthood.
ChrisQ. Doeand
Matthew P.5cottare
at the Departmentof
Molecular, Cellular
and Developmental
Biology, Universityof
Coloradoat Boulder,
Boulder, CO803090347, USA.
Segmentation gene expression in the nervous
system
Almost as striking as the striped pattern of
segmentation gene expression at the blastoderm
stage is the fact that most, perhaps all, of the
segmentation genes are expressed in internal tissues.
Transcript localization shows that most segmentation
genes are expressed in the embryonic CNS2°-z2'24'33.
Some segmentation gene transcripts have not been
detected in the CNS23,' 34 , but the resolution of the insitu hybridizations done in these studies may not have
been sufficient to detect transcription in a small,
© 1988,ElsevierPublications, Cambridge 0378-5912/88/$02.00
101
~i~ "~
products provides some clues. Experiments in grasshopper embryos indicate that the fate of each
neuroblast is determined at the time it enlarges, while
neuroblast l~rogeny are determined at the time of
their birth ~. The same is likely to be true in
Drosophila, although it has not been directly demonstrated. Most of the segmentation genes are initially
expressed in the Drosophila CNS during neuroblast
formation and the generation of neuronal progeny.
Using antibodies, the correlation between segmentation gene expression and the expected time of
neuronal determination can be examined with single
cell resolution. The segmentation gene en is
expressed in several neuroblasts at the time of their
enlargement (Doe, C. Q., unpublished observations),
while the product of the ftz segmentation gene is
observed in neuroblast progeny just as they are
born 28. Thus there appear to be tight temporal
correlations between en expression and neuroblast
determination and between ftz expression and the
determination of neuroblast progeny. Might individual
segmentation genes directly control specific features
of neuronal differentiation, such as axon morphology
or neurotransmitter type? This seems unlikely, as
several neurons that express ftz have been identified,
including interneurons and motoneurons, and no
common morphological features are apparent 28. The
fact that many segmentation genes are expressed
during neurogenesis suggests, by analogy to the
hierarchical network through which the same genes
act at the blastoderm stage, that interactions of
multiple regulatory gene products may be required to
direct neuronal determination. This type of model is
Fig. 1. Differences in the pattern of segmentation and homeotic gene given further support by the finding that more than
expression in the embryonic CNS. Embryos are dissected to reveal the CN5, one segmentation gene can be expressed within the
then stained with antibodies against either eve or Ubx proteins. (A) The same neuron (see below).
A
segmentation gene eve is expressed in the same identified neurons in every
segment; the sibling aCC and pCC neurons (upper arrowhead) and the RP2
neuron (lower arrowhead) are visible in this focal plane. Parasegment 6 (P56) is
indicated by the bracket. (B) The homeotic gene Ubx is expressed in a
segment-specific pattern, primarily in PSS- 12 (between arrows). Expression is
high in P56 (bracket), moderate in P57-12, low in PS5, and virtually no
expression is observed anterior to P55 (above top arrow). The eve antiserum
was kindly provided by IH. Frasch and/H. Levine, and the U bx monoclonal was
the gift of R. White and IH. Wilcox.
Segmentation gene function in the developing
nervous system
The mere presence of segmentation gene products
in the CNS does not demonstrate that they are
required for either the development or the continued
function of the nervous system. Unfortunately, it is
not simple to determine the function of a segmentation gene in the CNS. All of these genes are
expressed earlier in development to establish the
scattered subset of neurons. Antibodies that recog- pattern of segmentation. Mutants lacking this early
nize protein products of the segmentation genes ftz, expression have defects in segmentation, that lead to
eve, and en, show that each gene is expressed in a abnormal neurogenesis, thus masking neuronal
specific subset of neurons in every segment of the defects caused by the loss of subsequent CNS
developing CNS 35-37. Expression of segmentation expression. For segmentation genes whose blastogenes in the CNS is not merely due to inheritance of derm and CNS expression periods do not temporally
the blastoderm pattern by neuroblasts and neurons overlap, a temperature-sensitive allele should allow
derived from those blastoderm cells that expressed selective removal of CNS function. This approach has
these genes. For example, the pair-rule gene eve is been used to analyse the CNS function of the
expressed in alternate segments at the blastoderm segmentation gene eve (see below). A different
stage, but in every segment in the nervous system approach, used to study ftz CNS function, takes
(Fig. 1A). In addition to eve, many other gap, pair- advantage of the identification of c/s-acting regulatory
rule, and segment polarity genes show a different elements in the ftz promoter that specifically control
periodicity or pattern in the CNS than they do at the CNS expression 39. A modified gene has been conblastoderm stage. The differences between the blas- structed that provides the segmentation function offtz
toderm and CNS patterns may reflect separate but lacks the 5' sequences that are required for
mechanisms regulating segmentation gene expression normal levels of CNS expression. The engineered ftz
in the two tissues.
gene can provide near normal striped blastoderm
While little is known about the function of the expression, without detectable CNS expression ~8.
segmentation genes in the CNS, the timing of After this gene is introduced into the Drosophila
expression and distribution of segmentation gene germline, it can be crossed into an embryo that lacks
102
TINS, Vol. 11, No. 3, 1988
all normal ftz function, and the phenotype of embryos
specifically lackingf/z CNS expression can be determined. Identified neurons that normally express ftz are
still viable in these embryos. However, at least one
identified neuron, RP2 (Refs 40, 41), develops
abnormally. The RP2 motoneuron normally expresses
the segmentation gene eve and sends its axon to the
ipsilateral body wall of the embryo. When ftz CNS
function is removed, the RP2 neuron does not
express eve and its axon takes an aberrant contralateral trajectory28. These results indicate that at least
one function of ftz is to regulate eve expression in
certain neurons, and suggests that flz and/or eve
control the axon morphology of RP2.
The CNS function of eve has been assayed using a
temperature-sensitive eve allele. When embryos
homozygous for the eveIDw temperature-sensitive
allele 42 are raised at the permissive temperature until
the early eve blastoderm expression has occurred
(thus allowing normal segmentation), and then shifted
to the non-permissive temperature prior to eve CNS
expression, a selective loss of eve CNS function is
produced. In these embryos, some normally eveexpressing neurons, including the RP2 neuron, show
a transformed axon morphology (Doe, C.Q.,
Smouse, D. and Goodman, C. S., unpublished observations). The aberrant phenotype of the RP2 neuron
is similar in embryos lacking only eve CNS function and
in embryos lacking both ftz and eve CNS function,
suggesting that although ftz is required for eve
expression in RP2, it is the eve protein that regulates
RP2 axon morphology. These results, indicating that
f t z and eve gene products are involved in Drosophila
neuronal determination, are the first clear evidence
for function of segmentation genes in the CNS. The
results suggest that other segmentation genes may
have similar roles in the CNS.
homeotic genes are expressed. This was done initially
using in-situ hybridization for all of the genes of the
ANT-C and BX-C, and more recently with antibodies
to the Ubx, An~O and S c r homeotic proteins 48-5°'69. In
both epidermis and CNS, each gene is expressed
maximally in a specific parasegment (PS, a unit
composed of the posterior compartment of one
segment and the anterior compartment of the adjacent
segmentS1); some genes are also expressed at lower
levels in surrounding parasegments. For example,
Ubx is expressed maximally in PS6 (posterior third
thoracic and anterior first abdominal segments) and at
lower levels in PS5 and PS7-12 (Fig. 1B). An
important point is that unlike segmentation genes,
which are expressed in a stereotyped pattern in every
segment of the CNS, homeotic genes are expressed
in only some segments of the CNS, with segmentspecific patterns and levels of expression (compare
Fig. 1A with Fig. 1B).
Functions of homeotic genes in the developing
nervous s y s t e m
Although homeotic genes are transcribed early in
neurogenesis, they are unlikely to be involved in the
initial processes of neuronal determination. Many
features of neuronal differentiation, including the very
early expression of the segmentation genes and later
morphological features such as cell body position and
axon pathways, appear to be the same in every
segment. No homeotic gene is expressed in every
segment of the CNS, and thus no individual homeotic
gene can be required for specification of segmentally
reiterated features of neuronal differentiation. It is
possible, however, that different genes can serve the
same function in different segments. Therefore, the
segmentation genes (or as-yet unidentified genes)
may control development of segmentally reiterated
features of the CNS, while homeotic genes are
likely to regulate segment-specific CNS differenExpression of homeotic genes in the nervous
tiation.
system
Homeotic genes in the ANT-C and BX-C encode
Genetic evidence gathered over the last half proteins that contain the homeodomain, a 60 amino
century indicates that homeotic genes function in the acid, evolutionarily conserved sequence thought to be
epidermis to control segmental identity (reviewed in a DNA-binding domain on the basis of its similarity to
Refs 1-3). In-situ localization of homeotic gene bacterial and yeast DNA-binding proteins ~2'$3'7°. The
transcripts has verified that the RNAs are located in relation to DNA-binding proteins suggests that
the epidermal segments predicted by the genetic homeotic proteins may act as regulators of other
results. Antp transcripts, for example, accumulate genes by serving, for example, as transcription
primarily in some of the thoracic segments where factors. Which target genes might be regulated by
Antp mutants show defects, whereas Ubx transcripts
homeotic proteins in the CNS? As is discussed below,
accumulate mostly in the posterior thorax and anterior homeotic genes probably act in a cell autonomous
abdomen where the major defects are seen in Ubx fashion in the CNS to govern segment-specific differmutants 17'~8. A surprise, however, was that all entiation in a manner analogous to their function in the
homeotic genes examined were expressed at their epidermis.
highest levels in the embryonic CNS 17'18'25'43'44'69
The earliest segment-specific differences in the
(reviewed in Ref. 45). These observations raise CNS can be observed in the neuroblast pattern
several questions. Is the spatial distribution of homeo- between six and seven hours of development, as
tic gene products similar in the CNS and epidermis more neuroblasts develop in the thoracic segments
(and other tissues)? Do the regulatory mechanisms than in the abdominal segments (Ref. 27 and Doe,
controlling homeotic gene expression differ in each C, Q., unpublished observations). Homeotic genes
tissue? Are the target genes presumed to be regula- are expressed at this time; it is possible that one of
ted by homeotic gene products different in each the first functions of the homeotic genes in the CNS,
tissue? Does homeotic gene expression control or in its neuroectodermal precursor cells, is to control
segment-specific cell differentiation in the nervous development of the segment-specific pattern of
system, as it does in the epidermis?
neuroblasts. Potential targets of homeotic genes
A first step in approaching these questions is to might therefore include the neurogenic genes $4,
determine precisely when and where particular which regulate the number of neuroblasts formed.
TINS, Vol. 11, No. 3, 1988
103
antibodies that detect segmentspecific structures. Sensory neuron from the peripheral nervous
system (PNS) projections to the
CNS are especially suitable for
study due to their distinctive patterns in different segments. Each
adult appendage makes different
neuronal connections to the CNS.
PNS axons from wings, legs, and
halteres (halteres are vestigial
wings that serve as balancer
organs) all follow characteristic
pathways into the CNS, although
there are similarities in the projections of homologous neurons 6°'61
Changes in the wiring of the adult
PNS and CNS are caused by some
of the same homeotic mutations
that
visibly change the external
?
structures of the adult. The
changes are not due merely to
inductive effects on the transformed cuticle. Instead, the mutant
genotype of the neural cells is responsible for their altered morphology, as is shown most clearly by
Fig. 2. Neuronal transformations resulting from the loss of the genes of the BX-C. (A) Wild-type mosaic experiments in which only
third instar CN5 labelled with the monoclonal antibody 16F12 (Ref. 64). The six prospective leg
neuromeres in the thoracic ganglia (above arrow) and the lateral dots in the first abdominal ganglia part of ,the fly is mutant 6°. The
(arrow) are stained. Probable lateral clot homologs in the eighth and ninth abdominal ganglia are pattern of projections of PNS fibers
indicated (arrowhead). (B) CNS from a third instar larva lacking one copy of all the genes of the BX- from a homeofic mutant appendage
into the CNS depends both on the
C. Lateral dots are present in all abdominal ganglia. (Kindly provided by Alain Ghysen.)
genotype of the PNS cells and on
whether the CNS is wild-type or
Later steps in sculpting the segmental differences of mutant 6°, indicating that an alteration in the CNS has
the insect CNS, such as divergent morphologies of been caused by the homeotic mutation.
homologous cells29'ss, programmed cell death s6, and
To investigate further the function of the BX-C in
perhaps even the neural induction of segment-specific the larval and pupal CNS, a monoclonal antibody called
muscles s7, are also likely to be controlled in part by 16F12 was used 62-64. 16F12 stains the presumptive
homeotic genes.
leg neuromeres (PLN) of the CNS, structures that
While little is currently known about the functions are found only in the three thoracic segments (T1of homeotic genes in the embryonic CNS, one role T3). In the epidermis, a fly mutant for both Ubx and
that the genes clearly do play is to regulate each bxd genes of the BX-C shows a transformation of the
other. The simplest summary of the cross-regulatory anterior first abdominal segment (A1) into anterior
interactions is that genes expressed in more posterior T2, giving rise to extra T2-like legs on the normally
regions act as negative regulators of genes that are legless A1 segment. Correspondingly, in the CNS,
expressed in more anterior regions. Antp is primarily Ubx bxd double mutants develop an extra set of PLN
expressed in PS4 and PS5 of the CNS, but it is also in what would normally be A1, indicating its thoracic
expressed at lower levels in PS6-13 (Ref. 17 and identity. Thus one CNS function of these BX-C genes
Martinez-Arias, A., Akam, M.E., Bermingham,
is to suppress development of the PLNs in A1. By
J. R. and Scott, M. P., unpublished observations). In using weak mutations that give partial transformaembryos that lack the BX-C, Anfp expression is high tions, the changes in the CNS were shown to be
in PS4-1348,s°'s8 and thus it is the action of BX-C independent of the changes in the epidermis: the
genes that keeps A n ~ expression low in PS6-13. development of PLN was not necessarily linked to the
Similarly, the BX-C genes that are expressed and development of ectopic legs. The transformations in
function in the more posterior abdominal segments the CNS, therefore, are not due to inductive effects of
keep Ubx expression low in PS7-13. In the absence of the epidermis 64. More than one BX-C gene is
the abdominal BX-C genes, Ubx products are found at involved in regulation of PLN development. In A2,
high levels in PS6-13 sg. In addition to cross- PLN are seen only if both Ubx and another BX-C
regulatory interactions among themselves, the gene, iab-2, are mutated. Either gene is capable of
homeotic genes must regulate other genes, currently suppressing the PLN in A263. The 16F12 antibody
undiscovered, that control segment-specific neuronal also stains pairs of so-called lateral dots (LD), which
differentiation.
are CNS structures that are normally found only in
There is more information available about the T1, T2, T3, and A1 (Fig. 2A). Multiple genes control
effects of homeotic genes on the larval, pupal, and LD development, but in this case a single gene acts in
adult CNS than on the embryonic CNS, thanks mostly each segment. The prevention of LD development in
to the use of axon backfilling methods and monoclonal the posterior abdomen is due to the action of lab-2 in
104
TINS, VoL 11, No. 3, 1988
A2, another BX-C gene in A3-A6, and a third BX-C
function in A76s. When one copy of each of these
genes is absent, LDs can be observed in all of the
abdominal segments (Fig. 2B).
The effects of homeotic mutations on the nervous
system are particularly evident when identified
neurons are observed. This has been done not only
for the sensory neurons of the adult but also for an
adult CNS interneuron called the giant fiber. Normally, the giant fiber axon forms synapses only in T2.
However, in flies in which T3 is transformed into T2
by BX-C mutations, the giant fiber extends into the
transformed T3, and forms branches and synapses
there that duplicate its normal T2 morphology6s.
Thus, the giant fiber reveals the transformation of T3
to T2 by its duplicated axonal morphology. Because
the giant fiber cell body is in the brain, where the BXC is not active, its T3 synapses indicate the transformation of the T3 ganglia, not of the giant fiber itself.
Neurons are not always transformed into another
segment's pattern when the surrounding epidermis is
transformed - the PNS can develop independently. In
bx3 homozygous mutants (bx is a BX-C homeotic
mutation) the T3 cuticle is transformed to T2, but the
T3 PNS nonetheless forms a normal T3 pattern 61.
Using an antibody called 5D12 (isolated by Y. N. Jan
and L. Y. Jan), which recognizes segment-specific
fascicles in the pupal CNS, Teugels and Ghysen6a
found that bx alleles also have no detectable effect on
the CNS. Thus bx alleles transform T3 epidermis to a
T2 pattern, while the T3 CNS and PNS remains
unchanged. In contrast, abx alleles (another BX-C
mutation) will transform T3 cuticle to T2, with the
concomitant transformation of some T3 neurons to
the T2 pattern. The independent transformations of
epidermis versus neural cells produced by the bx
alleles could be due to incomplete gene inactivation by
the particular bx3 allele that was used, with epidermal
tissue being more sensitive than the PNS or CNS to
lowered gene function. Alternatively, the mutation
could specifically affect only epidermal expression.
Indeed, the bx3 mutation is known to alter the
distribution of Ubx protein in developing adult epidermis without noticeably altering the protein pattern in
the embryonic CNS67.
Tissue-specific regulation of homeotic and
segmentation genes
The anterior-posterior boundaries of expression
for each homeotic gene are not necessarily identical in
the mesoderm, epidermis, or CNS. For example, the
homeotic gene Ubx of the BX-C is expressed in PS6 in
the visceral mesoderm, PS6-12 in the somatic
mesoderm, PS5-12 in the CNS, and PS5-13 in the
epidermis is. Similarly, the genes Dfd, Scr and AnVp of
the ANT-C also show different spatial distributions in
each tissue (Ref. 44 and Martinez-Arias, A., Akam,
M. E., Bermingham, J. R. and Scott, M. P., unpublished observations). These observations suggest that
each tissue uses different regulatory mechanisms to
control the anterior-posterior boundaries of homeotic
gene expression.
Additional evidence for tissue-specific regulation of
homeotic genes is that each tissue exhibits qualitative
differences in the pattern and level of gene expression. For example, epidermal cells show a rough
gradient in the level of Ubx expression across a
TINS, Vol. 11, No. 3, 1988
parasegment ~. In the CNS, no simple gradient is
observed; individual neurons express a characteristic
level of Ubx in a complex pattern 28'46'47. In addition to
a more complex pattern of homeotic gene expression,
the CNS exhibits segment-specific modulation of the
level of homeotic gene products in homologous cells.
For example, in PS6, the identified pCC neuron has a
high level of Ubx protein, and its sibling aCC neuron
has a lower level; in PS7-12, however, the relative
abundance of Ubx protein in the two neurons is
reversed, with the aCC neuron having higher Ubx
expression than the pCC neuron 2s. Similar cellspecific modulation of neuronal expression is
observed for two other homeotic genes, Ant'p and
S c ~ , 5o.
Different genetic control systems for the epidermis
and the nervous system can also be inferred from BXC alleles, such as bx3, that affect just one tissue. Such
mutations could be indicative of: (1) different sets of
genes acting independently on the two tissue types;
(2) different tissue-specific splicing of transcripts; or
(3) the existence of tissue-specific c/s-acting elements
within the same gene or set of genes.
Tissue-specific control systems also regulate segmentation gene expression. The periodicity of segmentation gene expression is usually different in the
blastoderm and the CNS, indicating tissue-specific
control of the spatial patterns. Clearly the segmentation gene eve is regulated differently in blastoderm and
CNS tissues. During the blastoderm stage, loss offlz
function has no effect on eve expression 19, whereas in
the CNS, ftz is required for eve expression in at least
one neuron ~. The segmentation gene ftz is also
regulated differentially in the blastoderm and the
CNS, as is shown by the identification of tissuespecific c/s-acting sequences controlling the level of
expression in the blastoderm and CNS sg. Although
segmentation and homeotic genes are expressed in
both epidermis and CNS, it is not possible to
extrapolate regulatory interactions from one tissue to
another. It remains to be seen whether the interactions among segmentation and homeotic genes in the
Drosophila CNS can be used to predict the interactions among related genes expressed in the vertebrate CNS4-12.
Lewis 14 has proposed that the role of the BX-C
genes in the epidermis is to modify a 'ground state'
segment form, which he suggested was the T2
version of a segment. Indeed, in the absence of BX-C
function, the T3 and abdominal segments develop
epidermal structures similar to T2. The CNS may also
have a ground state, that is, a pattern of development
that occurs in the absence of any input from homeotic
genes. One function of Me homeotic genes would be
to modify this presumptive ground-state of the CNS
into segment-specific designs. What might determine
the archetypal neuronal pattern? The segmentation
genes are likely candidates, since they are expressed
very early in neurogenesis at the time when cell
determination occurs. At least two of these genes, ftz
and eve, play a role in controlling neuronal gene
expression and/or axonal morphology. Loss of the
CNS function of either gene produces a rather subtle
phenotype; this might reflect the limited number of
neuronal characteristics that were assayed. Alternatively, it is possible that many segmentation genes
may interact to govern neuronal determination, and
105
therefore the loss of one component may result in
only subtle alterations of the CNS. As more probes
for segmentation and homeotic gene products become
available, and as methods are developed for selectively modifying the CNS function of these genes, we
will learn more about the role of both segmentation
and homeotic genes during neurogenesis.
Implications for vertebrate neural
development
In the last two years, Drosophila segmentation and
homeotic genes have been used to isolate related
vertebrate genes, and all of these genes are
expressed in specific regions of the CNS, as well as in
other tissues. Some of the gene products show
remarkably precise localization in the CNS. For
example, the murine oncogene int-1, closely related
to the Drosophila segment polarity gene wingless9, is
expressed in a subset of neural cells at the lateral
edge of the embryonic neural plate l°'n. Similarly, the
Hox 1.3 protein is expressed in a subset of the
neuronal nuclei in adult mice, such as the pyramidal
cells of the hippocampus7. Although determining the
role of these genes in vertebrate neural development
may prove to be difficult, it should be aided by the
functional analysis of possibly homologous genes
expressed during Drosophila neurogenesis. An
increasing understanding of the molecular genetics
of Drosophila development, and in particular the
mechanisms of neuronal determination, may suggest
testable models for how vertebrate neural development is controlled, as well as provide molecular entry
points for studying neurogenesis in vertebrates.
Selected references
1 Scott, M. P. and O'Farrell, P. H. (1986) Annu. Rev. Cell Biol.
2, 49-80
2 Akam, M. (1987) Development 101, 1-22
3 Scott, M. P. and S. B. Carroll Cell (in press)
4 Awgulewitsch, A., Utset M. F., Hart, C. P., McGinnis, W.
and Ruddle, F. H. (1986) Nature 320, 328-355
5 Simeone, A. etal. (1986) Nature 320, 763-765
6 Carrasco, A. E. and Malacinski, G. M. (1987) Dev. Biol. 121,
69-81
70denwald, W. F. et al. (1987) Genes Dev. 1,482-496
8 Joyner, A. L. and Martin, G. R. (1987) Genes Dev. 1, 29-38
9 Rijsewijk, F. et aL (1987) Cell 50, 649-657
10 Wilkinson, D.G., Bailes, J.A. and McMahon, A. P. (1987)
Cell 50, 79-88
11 Shackleford, G. M. and Varmus, H. E. (1987) CellSO, 89-95
12 Krumlauf, R., Holland, P. W. H., McVey, J. H. and Hogan,
B. L. M. (1987) Development 99, 603-617
13 NLisslein-Volhard, C. and Wieshaus, E. (1980) Nature 287,
795-801
14 Lewis, E. B. (1978) Nature 276, 565-570
15 Kaufman, T.C., Lewis, R.A. and Wakimoto, B.T. (1980)
Genetics 94, 11 5-133
16 Hafen, E., Kuroiwa, A. and Gehring, W.J. (1984) Cell 37,
833-841
17 Levine, M., Hafen, E., Garber, R.L. and Gehring, W.J.,
(1983) EMBO J. 2, 2037-2046
18 Akam, M.E. and Martinez-Arias, A. (1985) EMBO J. 4,
1689-1700
19 Harding, K., Rushlow, C., Doyle, H. J., Hoey, T. and Levine,
M. (1986) Science 233,953-959
20 Baker, N. E. (1987) EMBOJ. 6, 1765-1773
21 Knipple, D. C., Seifert, E., Rosenberg, U.B., Preiss, A. and
J~.ckle, H. (1985) Nature 317, 40-44
22 Bopp, D., Burri, M., Baumgartner, S., Frigerio, G. and Noll, M.
(1986) Cell 47, 1033-1040
23 Kilchherr, F., Baumgartner, S., Bopp, D., Frei, E. and Noll, M.
(1986) Nature 321,493-499
106
24 Tautz, D. et al. (1987) Nature 327, 383-389
25 Chadwick, R. and McGinnis, W. (1987) EMBOJ. 6, 779-789
26 Kornberg, T., Sid~n, I., O'Farrell, P. and Simon, M. (1985)
Cell 40, 45-53
27 Hartenstein, V. and Campos-Ortega, J. A. (1984) RouxArch.
Dev. Biol. 193, 308-325
28 Doe, C. Q., Hiromi, Y., Gehring, W. J. and Goodman, C. S.
Science (in press)
29 Taghert, P. H. and Goodman, C.S. (1984) J. Neurosci. 4,
989-1000
30 Raper, J.A., Bastiani, M. and Goodman, C.S. (1983) J.
Neurosci. 3, 20-30
31 Doe, C. Q. and Goodman, C. S. (1985) Dev. BioL 111,193205
32 Bate, C. M. (1976) J. EmbryoL Exp. Morphol. 35, 107-135
33 MacDonald, P. M., Ingham, P. and Struhl, G. (1986) Cell 47,
721-734
34 Ingham, P. W., Howard, K. R. and Ish-Horowicz, D. (1985)
Nature 318, 439-445
35 DiNardo, S., Kuner, J. M., Theis, J. and O'Farrell, P. H. (1985)
Ceil 43, 59-69
36 Carroll, S. B. and Scott, M.P. (1985) Ce1143, 47-57
37 Frasch, M., Hoey, T., Rushlow, C., Doyle, H. and Levine, M.
(1987) EMBO J. 6, 749-759
38 Doe, C. Q. and Goodman, C. S. (1985) Dev. BioL 111,206219
39 Hiromi, Y., Kuroiwa, A. and Gehring, W. J. (1985) Cell 43,
603-613
40 Thomas, J. B., Bastiani, M. J., Bate, M. and Goodman, C. S.
(1984) Nature 310, 203-207
41 Patel,N. H., Snow, P. M. and Goodman, C. S. (1987) Ce1148,
975-988
42 N~isslein-Volhard, C., Kluding, H. and Jurgens, G. (1985)
Cold Spring Harbor Symp. Quant. BioL 50, 145-154
43 Kuroiwa, A., Kloter, U., Baumgartner, P. and Gehring, W. J.
(1985) EMBO J 4, 3757-3764
44 Martinez-Arias, A., Ingham, P. W., Scott, M. P. and Akam,
M. E., (1987) Development 100, 673--683
45 Scott, M. P. (1984) Trends Neurosci. 7, 221-223
46 White, R. A. H. and Wilcox, M. (1984) Ce1139, 163-171
47 Beachy, P.A., Helfand, S.L. and Hogness, D.S. (1985)
Nature 313,545-551
48 Carroll, S. B., Laymon, R. A., McCutcheon, M. A., Riley, P. D.
and Scott, M. P. (1986) Cell 47, 113-122
49 Wirz, J., Fessler, L. I. and Gehring, W. J. (1986) EMBO J. 5,
3327-3334
50 Riley, P. D, Carroll, S. B. and Scott, M. P. (1987) GenesDev.
1,716-730
51 Martinez-Arias, A. and Lawrence, P.A. (1985) Nature 313,
639-642
52 Laughon, A. and Scott, M. P. (1984) Nature 310, 25-31
53 Desplan, C., Theis, J. and O'Farrell, P. H. (1985) Nature318,
630-635
54 Lehmann, R., Jimenez, F., Dietrich, U. and Campos-Ortega,
J. A. (1983) Roux Arch. Dev. Biol. 192, 62-74
55 Bate, C.M., Goodman, C.S. and Spitzer, N.C. (1981) J.
Neurosci. 1, 103-112
56 Loer, C.M., Steeves, J. D. and Goodman, C.S. (1983) J.
Embryol. Exp. Morphol. 78, 169-182
57 Lawrence, P. A. and Johnston, P. (1986) Cell 45, 505-513
58 Hafen, E., Levine, M. and Gehring, W. J. (1984) Nature 307,
287-289
59 Struhl, G. and White, R. A. H, (1985) Cell 43, 507-519
60 Palka, J., Lawrence, P. A. and Hart, H. S. (1979) Dev. BioL
69, 549-575
61 Ghysen, A., Janson, R. and Santamaria, P. (1983) Dev. Biol.
99, 7-26
62 Ghysen, A., Jan, L. Y. and Jan, Y. N. (1985) Cell40, 943-948
63 Ghysen, A. and Lewis, E. B. (1986) RouxArch. Dev. Biol. 195,
203-209
64 Teugels, E. and Ghysen, A. (1983) Nature 304, 440-442
65 Thomas, J. B. and Wyman, R. J. (1984) Dev. Biol. 102,531533
66 Teugels, E. and Ghysen, A. (1985) Nature 314, 558-561
67 White, R. A. H. and Wilcox, M. (1985) Nature 318, 563-567
68 White, R. A. H. and Lehmann, R. (1986) Cell47, 311-321
69 Mahaffey, J. W. and Kaufman, T. C. (1987) Genetics 117,
51-60
70 Shephard, J. C. W., McGinnis, W., Carrasco, A.E.,
DeRobertis, E.M. and Gehring, W.J. (1984) Nature 310,
70-71
TINS, Vol. 11, No. 3, 1988