Download Homoeotic and atavic mutations in insects Two main types of

AMER. ZOOL., 17:613-629 (1977).
Homoeotic and atavic mutations in insects
A. GARCIA-BELLIDO
Centro de Biologia Molecular, C.S.I.C., Facultad de Ciencias, Universidad Autonoma,
Madrid, Spain
SYNOPSIS A comparative analysis of the known types of homoeotic mutants in insects
uncovers the existence of invariants in the homoeotic transformations. Mutations change
individual segments and individual compartments into one another leaving other developmental coordinates unchanged. Clonal analysis of some favorable mutants shows that
the homoeotically transformed organ or region (allotype) and the organ or region it mimics
(telotype) are developmentally identical. From this it is concluded that the function of the
wildtype allele is to repress the developmental characteristic of the telotype in the affected
organ or region (autotype). Since homoeotic mutations are specific to compartments and
double mutants show an additive effect, it is concluded that their wildtype genes act in a
combinatorial way, defining a given developmental pathway. The establishment and
maintenance of a given step in this pathway may be affected by mutations in different loci.
Genetic and developmental analyses of these mutations suggest that they are related in a
sequence of regulatory steps. The consideration of these findings leads to an operational
model for explaining genetic control of developmental pathways during ontogenesis and
evolution.
The first question which the study of variation may
be expected to answer relates to the origin of that
discontinuity of which species is the objective expression. Such discontinuity is not on the environment, may it not then, be in the living thing
itself? Bateson, 1894, p. 17.
INTRODUCTION
ters proper to other member of the series."
Homoeotic transformations arise by different mechanisms: genetic mutation,
teratogenic agents (phenocopies) and in
some instances following regeneration
such as heteromorphic regeneration or
transdetermination.
It is interesting when considering a
causal analysis of development, that the
homoeotic organ is identical in appearance
to the mimicked organ and thus possibly
constructed with the same genetic operations. It is the aim of the present work to
discuss some available data on homoeotic
transformations in insects, and more especially in Drosophila, under the conceptual
frame of gene function and regulation
during development and evolution.
Two main types of alterations of the
normal development may lead to abnormal morphogenesis: disruptive alterations
and homoeotic transformations. It is implied by this classification that the alteration leads to an interruption of the normal
developmental process in the first case,
whereas in the second a developmental
process becomes shifted from one pathway
into another. It is in this broad sense that
Bateson (1894) coined the word homoeosis
to include those morphological alterations,
"by which something has been changed
TYPES OF HOMOEOTIC TRANSFORMATIONS
into the likeness of something else, 'or
more specifically,' such variations which
Of all the homoeotic transformations,
consist in the assumption by one member the most reproducible and amenable to
of a meristic series, of the form or charac- study are those resulting from mutations.
Recent recompilations of homoeotic mutants known in insects can be found in
I am most thankful to my collaborators in the lab Gehring and Nothiger (1973), Ouweneel
for providing the material bases for the present
discussion. Drs. P. Ripoll and W. K. Baker are ac- (1970), Postlethwait and Schneiderman
(1974), Shearn (1976). For description of
knowledged for critical reading of the manuscript.
613
614
A. GARCI'A-BELLIDO
the mutants of Drosophila melanogaster and Mutants in other insects seem to follow
references see previous authors and similar rules. Thus in Tribolium sp. one
Lindsley and Grell (1968) unless otherwise labiopedia, one maxilopedia, two antennapedia
and one alate prothorax (similar to Hexapstated.
tera)
mutants have been reported
In the following discussion we will de(Sokoloff,
1966). It is interesting to notice
signate "autotype" the organ or region
which is transformed in the mutant and though, that the allotypic organ of
"allotype" the homoeotically transformed labiopedia corresponds to the telotype of
organ or region; the organ mimicked by the prothoracic leg (Daly and Sokoloff,
the homoeotic transformation will be 1965). A prenotal wing mutant is known in
called "telotype." A close examination Blatella germanica (Ross, 1964). A pseudoalof the known types of homoeotic trans- lelic series (E) of mutants similar to that of
formations caused by mutations reveals bithorax is known in Bombyx mori (Tazima,
certain general rules. Three main 1964). In Aedes sp. a proboscipedia (Quinn
generalizations will be first considered: 1) and Craig, 1971) and a mutation that
Homoeotic transformations remain in- transforms the palpus into antenna (Petvariant for certain anatomical coordinates terson et ai, quoted in Rai and Hartberg,
common or homologous in both autotype 1975) are known. The mutations arisand telotype. Thus, transformations are tapedia, antennapedia and abdominal legs,
within dorsal and ventral series of organs, (similar to bithoraxoid) are known in Musca
anterior and posterior regions, proximal (Milani, 1967) and bithorax and aristapedia
and distal regions, etc. 2) Most of the or Antennapedia mutants have been isolated
transformations are unidirectional, i.e., an in different species of Drosophila (Sturtevautotype is always transformed into the ant and Novitski, 1941; Spassky and Dobsame allotype. 3) Whatever the autotype, zhansky, 1950; Gloor and Kobel, 1966).
the allotype corresponds to the telotype of
There are to my knowledge only two
a thoracic segment, as a rule the mutations reported to cause a transformamesothoracic one. (Fig. 1).
tion from dorsal to ventral structures. The
ophtalmopedia
mutant is reported to transIn Drosophila melanogaster homoeotic
form
part
of
the
ommatidial region of the
transformations may affect both dorsal
and ventral anlagen of the same segment eye into leglike outgrowths (Gordon, 1934;
as in the mutants bithorax (bx), postbithoraxAbaturova and Ginter, 1968). Whereas the
(pbx) and engrailed (en), or, more common- former author only mentions the mutant,
ly, they affect either the dorsal or the the picture presented in the paper of the
ventral anlagen. In all cases the transfor- latter authors does not justify the nomenmation is invariant for dorsal or ventral clature. Outgrowths of undefined nature
characteristics. Moreover, in both dorsal are known in many mutants that deform
and ventral series of transformations the the eyes. The second mutant, podoptera,
different autotypic organs affected are described by Goldschmidt (1945), is
transformed into the same allotype. Thus, sufficiently documented in his drawings to
in the dorsal series, mutations like Opthtal- cast doubt on the interpretations of the
moptera (Opt), Hexaptera (Hx) and different transformation. This mutant found along
alleles of bithorax, transform respectively with tetraltera (Villee, 1942) which is still
the cephalic, prothoracic, metathoracic extant and very similar to it in phenotype,
and abdominal dorsal autotypic analgen shows variable dorso-ventral duplications
into something like (allotype) the dorsal of the costal region of the wing, along with
mesothoracic telotype. In the ventral series a reduction of the wing surface. This
the proboscis (proboscipedia, pb), the an- phenotype gives the impression of threetenna, Antennapedia (Antp), aristapedia (ssa), segmented leg (the three costal regions) in
Antennapedix (Apx), Nasobemia (Ns), 1(4)29, the extreme cases ("podoptera") and a
and the third thoracic leg and sternites reduced wing, apparently similar to a hal(bithorax alleles) are transformed into the tere ("tetraltera") in the weakest ones.
corresponding ventral mesothoracic (leg)
The rule that homoeotic mutations detype.
termine a unique transformation from one
615
HOMOEOTIC AND ATAVIC MUTATIONS IN INSECTS
6
O
K
O
G
HOMEOTIC
TRANSFORMATION
Opt
' CD (D Hx
HE
Dorsal
Disks
t a
HU
bx pbx
W
bxd
Df bx system
H
Tl 2 3 4 5 6 7
IE
SI 2 3 4 5 6 7
V D
SEGMENTAL
ORGANIZATION
Ventral
Disks
PB
AN PA
I
E
.,
Pb B
px
pbx
bxd
Df bx system
0
HOMEOTIC
TRANSFORMATION
(9
Antp.ss
,Msc
Pc
0 ? CDCD CD -
a.
FIG. 1. Homoeotic mutants of Drosophila melanogas- humerus; W: wing; H: haltere; PB: proboscis, AN:
ter and segments and compartments they affect. The antenna; PA: palpus; I, II, III: thoracic legs. 1-7
arrows indicate the direction of the transformation abdominal segments (T: tergites; S: sternites) G:
from the autotype to the telotype. The anlagen in the genitalia, CF: cephalic furrow. Mutant symbols
fate map of the blastoderm are HE: head; HU: explained in text.
single autotype into a single allotype has
exceptions. An interesting one is the mutant probosdpedia of Drosophila melanogaster
in which, depending on the temperature
of culture, the proboscis can be transformed into either a second leg or an
antenna (Vogt, 1946a). A homologous mu-
tation, probosdpedia of Aedes, transforms
both the labela into leg and the palpus into
antenna (Quinn and Craig, 1971). Two
different organs, the second and third leg,
show the chaetal pattern of the first leg in
the mutants Polycomb (Pc), Extra sex comb
(Esc), Multiple sex comb (Msc) and others of
616
A. GARCI'A-BELLIDO
Drosophila melanogaster (Hannah-Alava, 1973, 1976) demands a reconsideration of
1958). These mutations also represent an the concept of homoeotic changes as being
exception to the rule that segmental trans- exclusive to segmental transformations.
formations give a mesothoracic telotype. Mutants that transform one subsegment
In tumorous-head (tu-h) (Postlethwait et al., into another should be considered as
1972) spots of abdominal and genital homoeotic mutants. This situation is
structures appear in the head. It is interest- perhaps more clearly defined in the case of
ing that this mutation requires for its ex- the bithorax transformation of the dorsal
pression a mutant in the first chromosome metathorax. Two pseudoalleles of this
with maternal effects. The parallelism be- series transform either only the anterior
tween tu-h and the mutation bicaudal (Bull, (bx3) or the posterior (pbx) part of the
1966) that maternally determines the segment (Lewis, 1963). These regions are
transformation of the anterior segments now known to correspond to the two earinto abdominal ones, is intriguing. Lethal liest compartments of the thoracic segfactors can show, in implants of their ments.
imaginal disks, homoeotic transformations.
Other alleles of bx preferentially affect
Thus, the lethal 1(4)29 determines, to- either proximal compartments, notum regether with a change of the antenna into gion in bx,1 or distal ones, wing in bs34*1
second leg, malformations in the second (Lewis, personal communication). The
and third thoracic legs (Gehring, 1970). mutation engrailed (en) transforms posteSimilarly 1(3)111-10 and 1(3)XVI-18 show rior regions into anterior ones, both in
together with a transformation of part of dorsal and ventral thoracic disks (Garciathe haltere into wing, transformation of Bellido and Santamaria, 1972). The only
the genital disk into leg structures (Shearn, mutant allele known at this locus affects
1974).
preferentially distal regions (wing, basitarStudies going beyond the general de- sus) of the thoracic appendages. As description of the segment or appendage scribed before, tetraltera (let) shows a transaffected and the type of the transforma- formation of the ventral region of the
tion have been carried out only with few dorsal mesothorax (pleura), into the corhomoeotic mutants. The different muta- responding dorsal ones and as a consetions of Drosophila melanogaster leading to aquence the reduction of the wing appendtransformation of the antenna into leg age to a club, only superficially resembling a
may transform distal or proximal joints or haltere (Garcia-Bellido, unpublished). A
both into the corresponding distal or prox- homologous transformation can be deimal joints of the mesothoracic leg (Gehr- tected on the dorsal metathoracic segment.
ing, 1969). Thus, whereas Nasobemia, an This seems to be also the phenotype of a
extreme allele of Antennapedia, transforms recently discovered mutant, wingless (uigl)
the entire antenna and adjacent cephalic (Morata and Lawrence, 1977).
surface into a complete leg, including
Thus, the partial transformation caused
sternopleural region, coxa, and the re- by the known homoeotic mutations
maining distal joints, other Antennapedia suggests the existence of developmental
alleles and 1(4)29 transform only proximal pathways within the same organ that can
joints. The known mutations of the ssa be independently affected by mutation.
locus transform only distal joints of the We will analyze below whether these reantenna into joints distal to the basitarsus. gional transformations reflect the exisA comparative analysis of these transfor- tence of specific genes or alleles affecting
mations allows us to construct a homology regional developmental pathways or
map of the antennal and leg joints or whether they are due to incomplete exsegments (Gehring, 1969; Postlethwait and pressivity and consequently specificity in
Schneiderman, 1971).
the transformation.
The discovery of the existence of de1
velopmental compartments or sub-regions
More detailed reviews on homoeosis are marked
in a given segment (Garcia-Bellido et al., with an asterisk in the list of references.
HOMOEOTIC AND ATAVIC MUTATIONS IN INSECTS
A word of caution is however needed.
Most of the homoeotic mutations found so
far were detected in viable individuals. It is
therefore questionable whether the men* tioned transformation rules will apply to
other transformations incompatible with
viability. In fact other types of homoeotic
transformations not caused by mutation
seem not to follow the above mentioned
restrictions.
Homoeotic changes also may result from
experimental intervention during development. Regenerative heteromorphosis
is a common phenomenon in Crustacea
and lower insects (Przibram, 1910). In a
similar way teratogenic agents cause
phenocopies of known homoeotic mutants
(Goldschmidt and Piternick, 1957). Also in
those instances the transformation seems
to be unidirectional and univocal. In
Drosophila, following fragmentation and
culture of antennal imaginal disk in a
metamorphosing host, leg structures appeared in the implant after metamorphosis, instead of the autotypic antennal
ones, possibly as a consequence of
homoeotic regeneration (Vogt, 1944). If
regeneration, fragmentation and culture
in vivo are repeated before metamorphosis, the inventory of allotypic structures increases. This phenomenon has
been named
"transdetermination"
(Hadorn, 1966). In transdetermination
there are perferential sequences of transformations but they can be multidirectional and even reciprocal. They certainly
do not respect the dorsal-ventral serial
restriction. In fact transdetermination
from leg to wing and vice versa is frequent.
As a rule these allotypic territories appear
in small groups of cells and occasionally in
disarranged patterns. It is possible that
some transformations, caused by homoeotic mutations, correspond to transdetermination, as a consequence of extra proliferation following cell death during development (see Ouweneel, 1970).
DEVELOPMENTAL CHARACTERISTICS OF THE
HOMOEOTIC MUTANTS
The apparent transformation of one
organ into another does not denote, in
617
itself, a similarity in their origin and
mechanisms of development. A developmental analysis of the homoeotic mutants
has been approached only in a few instances. In all these cases allotype and
telotype seem to be developmentally identical.
Cell recognition has been shown to be a
very specific property of dissociated cells
from different imaginal disks. It is inferred from their behaviour that the isolated
epidermal cells have cell surface labels
corresponding not only to the imaginal
disk but also to the region or compartment
from which they were derived (see
Garcia-Bellido, 1972, for review). In combinations between wildtype cells from a
given imaginal disk (autotype) and its
homoeotic derivatives (allotype), both
kinds of cells segregate in reaggregates.
The same allotypic cells will however integrate in mosaic with wildtype cells of the
telotypic disk. This has been shown to be
the case with Antennapedia (Antp50) and
aristapedia (ssa and ssa40a) antennal cells
(Garcia-Bellido, 1968), with cells of the
haltere disk of different alleles of the
bithorax system (Garcia-Bellido and Lewis,
1976), with the cells of the posterior wing
of engrailed (Garcia-Bellido and Santamaria, 1972) and with cells of the outgrowth of the eye disks of Ophtalmoptera
(Garcia-Bellido, unpublished). These
findings suggest that the homoeotic mutation expressed itself in a change in the cell
recognition properties of the transformed
cells.
Other cell behaviour properties indicate
that the development of the homoeotic
transformations (allotype) is similar to that
of the telotypic organs they mimic. Cell
lineage analysis of the allotypic organ,
based on the behaviour of mitotic recombination clones of cell marker mutants, has
been carried out in some mutants.
In bithorax-postbithorax (bx3pbx) flies the
number of founder cells in the haltere
(dorsal metathoracic) anlage is similar to
that of the wing (dorsal mesothoracic) anlage but different from the number of
founder cells in the haltere anlage of
wildtype individuals. During subsequent
development cell proliferation rate, re-
618
A. GARCI'A-BELLIDO
gional mitotic orientations, developmental autotype by the allotype on an otherwise
compartmentalization and final cuticular perfectly integrated pattern, i.e., the transdifferentiation are indistinguishable in formed tissue retains all the spatial and
both dorsal mesothoracic disk and temporal developmental coordinates of
homoeotic dorsal metathoracic disk the tissue which substitutes. The same be(Morata and Garcia-Bellido, 1976). In Con- haviour has been shown to occur in other
trabithorax, a mutant that causes a variable morphogenetic mosaics of engrailed in the
transformation of the dorsal mesothoracic first leg (Tokunaga, 1961), in the wing
structures into those typical of the (Garcia-Bellido and Santamaria, 1972,
metathoracic one, the expressivity of the Morata and Lawrence, 1975) of different
transformation is incomplete. Cell lineage alleles of the bithorax system in the haltere
analysis has shown that the proliferating (Lewis, 1964, Morata and Garcia-Bellido,
cells are expressing identical growth prop- 1976), and of aristapedia in the antenna
erties to that of the posterior metathorax, (Postlethwait and Girton, 1974). In the
where the expressivity of the transforma- case of engrailed (Morata and Lawrence,
tion is total. However, clones in the an- 1975) and in bithorax (Morata and Garciaterior region where the expressivity of the Bellido, 1976) it could also be shown that
transformation is incomplete show that the the mutant recombinant clones showed
cell penetrance of the mutant is not clonal, throughout development the same recogand varies throughout development nition properties and affinities detected in
cell aggregation experiments described
(Morata, 1975).
A somehow different situation has been above.
The forementioned findings, taken as a
claimed to occur in the Antennapedia transformation. In this case the data of cell whole, strongly suggest that 1) the
lineage analysis have been interpreted as homoeotic tissue has the same developsuggesting that the antennal anlage grows mental properties of the telotypic tissue it
like an antenna wildtype disk, except at the mimics throughout development; 2) the
end of development, when the transfor- homoeotic transformation results from a
mation is thought to take place (Post- substitution or shift of one developmental
lethwait and Schneiderman, 1969, 1971). pathway by another, 3) this transformation
Since the Antp allele studied has weak expresses itself autonomously in cells, and
expressivity, it would not be surprising to 4) the function of the wildtype alleles of
uncover, by the same analysis using these mutations is required throughout
stronger alleles, an earlier effect of the development in order to maintain the autransformation. Similar analyses carried totypic developmental pathway.
out on engrailed, a weak allele, show again It must be realised that these conclusions
that its incomplete expressivity is based on were derived from the study of a few
variable, not clonal, cell penetrance homoeotic mutations. It is not impossible,
(Garcia-Bellido and Santamaria, 1972).
in fact it is even probable, that other
The study of morphogenetic mosaics of homoeotic transformations do not behave
homozygous mutant tissue, resulting from in the same way. This is precisely expected
mitotic recombination in heterozygous from those transformations that may occur
flies, corroborates previous conclusions. following cell death and extra proliferaThe work of Stern and his students on tion, leading to the appearance of allotypic
genetic mosaics of pattern mutants has tissue by a causal mechanism similar to that
been extended to some homoeotic mutants leading to transdetermination. This possirecently. Roberts (1964) already showed bility should be kept in mind when we try
that homozygous recombinant clones of to understand the developmental effect of
aristapedia (ssa) showed the autonomous the homoeotic mutations.
transformation of antenna into leg. It was
Most of the mutants genetically and dethen clear, for the first time, that the velopmentally analyzed so far are viable
homoeotic mutant character 1) could be and show the mutant phenotype in
cell autonomous and 2) would substitute the homozygous or heterozygous condition. It
HOMOEOTIC AND ATAV1C MUTATIONS IN INSECTS
is to be assumed that other alleles of these
genes or other homoeotic mutants will be
lethal in homozygous condition and
wildtype in the heterozygous one. The
isolation and characterization of lethal
morphogenetic mutants is now possible by
making use of temperature sensitive alleles
(Suzuki, 1970), of transplantation techniques of imaginal disks of lethals, (Shearn
et al., 1971; Stewart et al., 1972) or of
mitotic recombination (Ripoll and
Garcia-Bellido, 1973; Garcia-Bellido and
Dapena, 1974; Ferrus and Garcia-Bellido,
1976). It is hoped that when we incorporate lethals into our study a clearer picture
of the types and role of homoeotic mutations will be obtained.
GENETIC PROPERTIES OF THE HOMOEOTIC
MUTATIONS
Formally expressed, certain homoeotic
mutations seem to cause a substitution of
one developmental pathway by another.
However, the nature of these pathways is
still unclear. Developmental pathways
have been related to developmental compartments (see Garcia-Bellido, 1975a).
The development of the imaginal disks
seems to proceed by a series of successive
binary subdivisions of the population of
cells into compartments. In the adult these
compartments appear to be delimited by
constant well defined borders. Cell lineage
studies have shown that the number of
cells, the mitotic rate and the preferential
mitotic orientations of the proliferating
cells are characteristic of compartments.
This has been shown to be the case in the
development of the dorsal mesothoracic
disk (Garcia-Bellido et al., 1973) the dorsal
metathoracic disk (Morata and GarciaBellido, 1976) the thoracic legs (Steiner,
1976), the head (Baker, 1977) and the
genital disk of both sexes (Nothiger, personal communication).
It is therefore remarkable to find that
the extent of the transformation of some
homoeotic mutants is restricted to the
limits of developmental compartments.
Therefore compartments can be considered as phenotypic units, that may be affected as a whole by mutation in a compar-
619
able way to enzymatic steps in a metabolic
pathway. Now a series of questions, such as
the nature of gene function, allelic expression, regulatory gene interactions, etc., can
be posed for a predefined developmental
process. We will now analyze some of these
problems in relation to mutants which
have been or are now under study.
Many homoeotic mutants show a variable penetrance, expressivity and specificity in the manifestation of the transformation. This variability is increased
under experimental conditions such as
temperature, X-irradiation, nutritive conditions and genetic background. This variable behaviour led previous investigators
to interpret the homoeotic transformation
as resulting from unspecific alterations in
growth and the corresponding homoeotic
mutations as disruptive ones (Villee 1946a,
Waddington, 1962). The opposite idea that
homoeotic mutations, at least some of
them, correspond to blocks in discrete developmental pathways derives from both
the genetic analysis of these mutations and
the specific restrictions the mutant alleles
show in their transformations. This situation is clear in the case of the mutants of
the bithorax complex, genetically studied by
Lewis (see Lewis, 1963, for older references). Of the'bithorax (bx) locus different
alleles are known which differ in the extent
of their transformation. These transformations are however restricted to the anterior compartments of both dorsal and
ventral metathoracic disks. The variable
expressivity of those alleles can be interpreted as due to some remnant wildtype
function in the mutant products. In fact,
genetic analysis shows that they behave as
hypomorphs: they are more extreme when
heterozygous with a deficiency and are
fully recessive in two doses of mutant and
one of wildtype. The strongest allele
known, bx3 shows in bx3/Df(bx) flies an almost complete transformation. In these
flies the wing-haltere separation cleanly
coincides with the anterior-posterior demarcation line of the wing and haltere
compartments. Some other ten alleles are
known, all weaker than bx3, whose expressivity can be modified by temperature (Villee, 19456) and by possible physiological
620
A. GARCIA-BELLIDO
enhancers and suppressors (Kaufman et al.
1973). In all cases the transformation is
restricted to the anterior compartment of
the involved segments.
As mentioned above, some of the alleles
of bx differ in the regional specificity of the
transformation. They may affect preferentially the notum (foe1) or the haltere compartment (bs34e). It is not yet known
whether this specificity is due to genetic
modifiers or reveals a further complexity
of the bx locus determining functions
specific for proximal or distal subcompartments of the anterior one.
In the pbx locus two alleles are known.
The first one found behaves almost like an
amorphic mutation. The homozygous flies
show a complete transformation of the
posterior compartment similar to that of
pbxlDf(pbx) flies. The second allele found,
pbx2, is weaker showing no apparent specificity within the posterior compartment.
The effect of bx and pbx are completely
additive. The bx3 pbxlDf(bx pbx) flies show a
complete transformation of the entire
metathorax into mesothorax. This is also
the phenotype of Ultrabithorax (Ubx) point
mutations. Although homozygous Ubx flies
are lethal, the transformation can be
studied in either the larval stages, in larval
structures such as tracheation, segmental
hooks, etc. (Lewis, personal communication), or in mitotic recombination clones
(Morata and Garcia-Bellido, 1976). Lewis
(1967) postulated that these point mutations in the Ubx locus correspond to mutations in the operator or promotor locus of
the complete bithorax complex. In fact, Ubx
point mutations or chromosome rearrangements with breakpoints to the left
of or at the 89E1-2 doublet behave in
genetic tests as the deficiency for the entire
bithorax complex. Both point mutations
and deficiencies are dominant and show in
heterozygous condition a slight morphological effect in the metathorax which
disappears with two doses of wildtype
genes.
Other mutations in this complex, however, behave as dominants over one or
several doses of wildtype genes. The
phenotype of those mutations is that of a
transformation of the mesothorax back
into that of the metathorax. Two mutations are known, Contrabithorax (Cbx) and
Haltere mimic (Hm). Cbx is a point mutation
which maps closely to Ubx, whereas Hm is a
rearrangement with a breakpoint in the bx
region. They can be operationally considered as mutations in the operator site of
the complex, leading to a constitutive derepression of the bithorax genes (see below). As expected from such a model, bx3
Cbx flies have a wildtype phenotype in the
mesothorax (Lewis, 1964). Both mutants
differ in their expressivity. Whereas Cbx
affects mainly the posterior compartment,
although it can transform both anterior
and posterior compartments, the Hm transformation has a remarkable specificity for
distal region in both anterior and posterior
compartments. Genetic analysis has
shown, though, that the derepressed condition of Cbx is not total and this could
explain the variability of its expression and
possibly of its specificity, as mentioned
above (see Morata, 1975).
The function of the bithorax complex in
the metathorax can now be inferred from
the phenotype of its amorphic condition.
Since in its absence the metathorax is
transformed into mesothorax it is reasonable to assume that the wildtype products
of its genes are necessary to maintain a
metathoracic pathway instead of a
mesothoracic one. Since these mutations
do not lead to a disruptive block of a
developmental pathway, but rather to a
shift into another one, Lewis (1963) postulated that the specific function of the
bithorax wildtype genes was to prevent the
mesothoracic pathway to be operative in
the metathorax. It should be added that
the metathoracic pathway does dominate
over the mesathoracic one, i.e., that the
wildtype function of bithorax is epistatic
over that of the genes defining the
mesothoracic pathway, a hypothesis that
explains the phenotype of the Cbx and Hm
mutations.
Other mutants are known in the bithorax
complex that specifically affect the abdominal segments transforming them into
thoracic ones and affecting both dorsal
and ventral imaginal disks also (Lewis,
personal communication). The bithorax
HOMOEOTIC AND ATAVIC M L ' T A T I O N S IN INSECTS
gene complex seems thus to be involved in
the control of the segmental specificity of
the metathoracic and abdominal developmental pathways. There are within it different gene functions, separable by mutation, recombination and chromosomal
rearrangement, which control segmental
as well as compartmental pathways.
A combined genetic and developmental
analysis has permitted the identification in
the bithorax transformation, of 1) the range
of action of its wild type products and 2)
the genetic nature of its mutations. We do
not have in any other homoeotic transformation such a combination of genetic and
developmental data. However the available data on other mutations seem to conform to the same scheme.
Only a single mutant allele is known at
the engrailed (en) locus. It is fully recessive
and in homozygous condition in all the
thoracic segments and in both ventral and
dorsal imaginal disks it causes mirror
image duplication of some structures typical of anterior compartments to appear in
posterior compartments (Garcia-Bellido
and Santamaria, 1972). The transformation of en is incomplete. In the dorsal
mesothoracic disk it is only clearly expressed in the venation pattern and in chaetes
of the wing margin. It was assumed that
this incomplete expressivity is due to the
hypomorphic nature of this allele. In fact
the expressivity for that transformation
can be modified by temperature and by
combining it with Minutes (Morata and
Lawrence, 1975). Even under these conditions the transformation remains limited
to the distal compartments. Genetic
analysis of more alleles will eventually
allow us to know if the regional specificity
of the present allele is due to the low
expressivity of the allele or to the existence
of other loci with compartment specificity
organized in a pseudoallelic series, like the
one of bithorax.
The function of the wild type allele of
engrailed can be understood, by analogy
with that of bithorax, as involved in the
maintenance of a posterior developmental pathway instead of'an anterior one, in
the segments where such a posterior pathway exists. This interpretation is consistent
621
with the phenotype shown by double mutants. In en pbx flies the posterior wing
appearing in the metathoracic segment is
now transformed into an anterior one.
This finding suggests ,that the posterior
properties shown by the mutant cells do
not derive from migration of cells of the
anterior compartment into the posterior
one or by copy of the posterior cells of the
anterior pattern. It rather suggests, that en
represents a mutation that leads to a pathway substitution, uncovering an anterior
instead of a posterior developmental
pathway (Garcia-Bellido and Santamaria,
1972; Morata and Lawrence, 1975).
Among the mutants of the ventral series
of transformations we will only consider
here those originated by mutations in the
Antennapedia (Antp) and aristapedia (ssa) loci,
for these are the only ones where some
genetic analysis has been done.
Several mutants are known in the Antp
locus corresponding to point mutations
and to chromosomal rearrangements. All
of them are characterized by being dominant and homozygous lethals (Denell,
1973). The expressivity is variable among
alleles, depending on culture conditions.
All of them cause a more or less large
transformation of all the antennal segments of the antenna appendage into the
homologous segments of the second
thoracic leg. In certain Antp combinations
the transformation is into complete second
leg, from sternopleura to claws. In PclAntp
heterozygotes this leg is transformed into a
first leg with sexcombs in males. The developmental interpretation of these mutants is, although apparently obvious from
the phenotype, difficult in view of developmental as well as genetic considerations. There are no indications of posterior
compartments-in the head (Baker, 1977)
whereas they exist in the thoracic legs
(Steiner, 1976). Thus, the allotypic leg in
the antenna should contain only elements
of the anterior compartment, or represent
an anterior-anterior duplication. The latter is improbable because the PclAntp flies
have only a single sexcomb, possibly corresponding to that of one single compartment.
Genetic arguments make difficult a
622
A. GARCIA-BELLIDO
functional interpretation of these mutants.
The mutant phenotype does not correspond to the haploinsufficiency of this
locus, because the deficiency of this locus
has a wildtype phenotype in heterozygotes
(Denell, 1973). The dominant effect could
otherwise be interpreted as due to an
operator constitutive mutation which
would lead to the derepressed synthesis of
a gene product whose normal function is
to be interpreted as blocking an antenna
developmental pathway and substituting it
by a leg pathway. This in turn would mean
that the latter pathway is hypostatic to the
former, an hypothesis which is inprobable
in view of other considerations (see below).
An alternative explanation is that Antp
mutations have an effect not related to the
normal function of its wildtype allele. This
effect could result from the accumulation
of deletereous products on unrelated developmental pathways. In fact the Antp
mutants behave genetically as antimorphic
mutations (Denell, 1973). For this reason it
is imperative to know the cellular
phenotype of the deficiency of this gene in
embryos or in mitotic recombination
clones.
ered as an indication that the homoeotic
transformation may result in nonspecific
alterations in the normal developmental
pathway of the antenna anlage.
Similar difficulties to that of Antp arise in
the study of other serial transformations
such as Ophtalmoptera and Hexaptera (see
Garcia-Bellido, 19756 for further discussion).
GENETIC AND DEVELOPMENTAL INTERACTIONS
BETWEEN HOMOEOTIC GENES
The same allotypic transformation appearing in the same autotypic organ has
been found to be caused by mutations in
different loci. This is the case of Antp, ssa
and 1(4)29, of tet and wgl, of Pc, Msc and
Esc, of the bithorax complex, Rg-pbx,
Df(3)red, 1 (3)111-10 and 1(3)XVI-18. It is
interesting to notice that in these
homologous mutations there are loci with
dominant and loci with recessive mutant
alleles. Moreover, in some cases external
agents, applied at characteristic developmental stages, lead to transformations that
phenocopy the same mutant effect. Thus
phenocopies of ss* (Bodenstein and
Abdel-Malek,
1949; Sang and McDonald,
Similar considerations make difficult the
interpretation of the aristapedia (ssa) 1959; Gehring, 1964, etc.) and of bithorax
phenotype. All the mutant alleles known (Maas, 1949; Gloor, 1947) have been reare recessive and the flies heterozygous for ported. These facts lead logically to the
a deficiency are phenotypically normal. question of how genes interact during deThese mutations cause a partial transfor- velopment and how phenocopies alter
mation of the distal segments of the an- these developmental pathways.
tenna into those homologous to the leg.
This analysis has been initiated with the
The transformation is restricted to seg- genes related to the metathoracic and
ments distal to the basitarsus, even in ssal mesothoracic pathways. Lewis found two
Df(ss) flies. However, clonal analysis of the mutant factors located outside of the
leg does not uncover a compartment bithorax locus, one associated with a reboundary in that segment (Steiner, 1976). arrangement, Rg-pbx, and another with a
We do not know then why the transforma- deficiency, Df(3)red, which interfere with
tion is specifically restricted to that distal the expression of the bithorax genes. Rg-pbx
region. Moreover all the aristapedia alleles is a dominant factor, with incomplete
ol Drosophila melanogaster are allelic to 55, apenetrance, which produces in flies
mutant that reduces the size of the chaetes homozygous for bx+ and pbx+ a variegated
and it is difficult to understand on simple pbx phenotype. However, the penetrance
bases the relationships between the ss and of this transformation varies with increasssa phenotypes. The most disturbing fact, ing number of doses of these genes (Lewis,
however, is the observation by Wad- 1968). He postulated that its effect can be
dington and Clayton (1953) that the ssa compared to that of a superrepressor muallele also affects the segmentation of the tation and designated the corresponding
thoracic legs. This finding must be consid- wildtype allele Regulator of pbx. Df(3)red,
HOMOEOTIC AND ATAVIC MUTATIONS IN INSECTS
623
lacking two or three bands of the salivary Bellido, 1974 and unpublished results). It
chromosome, behaves in a similar way. In was then concluded that the bithorax
homozygous bx+ flies this deficiency has a phenocopies resulted from interference
dominant effect leading to the appearance with the mechanism of activation of the
of a variegated bx phenotype, and in addi- bithorax complex, not with the mechanism
tion in flies heterozygous for Df(bx,pbx) it of expression of its gene products. The
produces a pbx effect. Lewis postulated effect of ether was interpreted as causing a
that this deficiency is lacking a factor shift of the positional cues of the egg
necessary for the expression of the wild cortex. That conclusion is reinforced by
type bithorax genes.
the observation that the zygotic sensitivity
The discovery that bithorax phenocopies, to phenocopies decreases with an increase
produced by ether treatment of blas- in number of doses of wildtype bithorax
toderm embryos, have a clonal manifesta- systems present in the genome. This obtion (Capdevila and Garcia-Bellido, 1974) servation strongly suggests that, 1) the
opened the way to a series of genetic and activation of the bithorax genes results
developmental studies about the mecha- from a negative control of regulation,
nism of activation of the bithorax genes. It namely from the lack of repression in the
was shown that irrespective of the genetic cells of the metathoracic region, 2) the
constitution of the mother, flies physical basis of the cell heritable
heterozygous for mutant alleles in the phenocopy lies in the bithorax region and
structural loci (bx1, bx3, pbx, bxd) do have thenot in cytoplasmic properties of the
same frequency of phenocopies as wild treated cells, and 3) the target region of
type flies. However flies heterozygous for a the repression is the operator region of the
Ubx rearrangement (Ubx130) or for the de- system, the intact Ubx locus (Fig. 2).
ficiency of the whole complex have a freWe have analysed the sensitivity to
quency of phenocopies double that of wild phenocopies of mutations in other loci that
type controls (Capdevila and Garcia- modify the bithorax expression, in order to
DEVELOPMENTAL
PATHWAVS
Realisators
bx complex
Selector
Rg-bx (?)
Activator
^ ,
.
A
A A A
A A A A A A A
, _
Df(3)red(?)
Cortex
FIG. 2. Possible genes involved in the mechanism of
segregation of the metathoracic (MT) and
mesothoracic (MS) pathways. Triangles: inductor
molecules (i), arrows: transcription-translation steps,
Rectangles: operator regions in on (open) or off
(closed) position. Gene symbols explained in text.
624
A. GARCIA-BELLIDO
distinguish whether they act on the
mechanism of repression of bithorax or
affect the expression of its gene products.
It is expected that those affecting the
mechanism of activation will alter the
phenocopy frequency, whereas those affecting the expression of their gene products will not. Embryos heterozygous for
Rg-pbx show a higher frequency (more
than double) of phenocopies than wildtype
controls. This is consistent with the superrepressor properties of the mutant as
suggested by Lewis. It is interesting to note
that the variable expression ("variegated")
of this mutation also has a clonal basis, i.e.,
mitotic recombination clones of cell
marker mutants in a Rg-pbx haltere are
restricted to either the non-transformed
haltere or the homoeotic wing territory
without crossing the histotypic boundary.
This is a strong indication that its time of
action is during the embryonic activation
of the bithorax complex, probably at the
same time of the phenocopy effect.
Phenocopy frequencies are similar in
Rg-pbx zygotes no matter if this factor is
carried to the zygote by the egg or the
sperm (Capdevila, personal communication).
Embryos heterozygous for Df(3)red show
a large increase (more than 4 times) in the
frequency of phenocopies relative to controls if the mother was heterozygous for
this deficiency. The increase is lower (less
than 2 times) if it is introduced into the egg
by the sperm. This maternal effect can be
interpreted as due to an insufficiency of
gene products required for the specification of the segment, i.e., a depletion of
inductors, therefore working in an additive way with the ether effect on the cortex
of the egg (Fig. 2) (Capdevila and GarciaBellido, in preparation).
The mutations 1(3)111-10 and 1(3)XVI18 on the other hand do not affect the
frequency of phenocopies. This is consistent with the finding that they show patchy
transformations in mitotic recombination
clones and suggests that they may interfere
with the expression of the bithorax complex, (Capdevila, personal communication). Moreover it has been shown that
these lethals affect the normal develop-
ment of other organs, like the genital disk,
which are not affected by the bithorax mutants (Shearn, 1974).
It is obvious from the foregoing discussion that much work is still needed before
a complete picture of the mechanism of
bithorax activation can be drawn. It is
hoped that similar genetic and developmental analysis on other homoeotic mutant systems will help us to understand the
role of their wildtype alleles in the genetic
control of the corresponding steps of a
given developmental pathway. The data so
far available, however, suggest that the
mutants which show a similar phenotype
can be assigned to genes acting in a sequence of events leading to the control of a
given step.
Garcia-Bellido (1975a) proposed that
the genetic control of a given step in a
pathway requires a series of signals
emanating from different genes. These
genes seem to control these steps at different levels. The reading of position takes
place perhaps by an interaction of a repressor (product of an "activator" gene)
with a differentially distributed inductor.
The absence of repressor leads to the
genetic activation of a gene ("selector"),
that in turn controls the pathway via the
continuous synthesis of its products
throughout successive cell generations.
How these gene products control the corresponding pathway is not known. I proposed that this is by the specific activation
of other genes ("realisators") which define
morphogenetic cell properties, such as
mitotic rate and orientation, specific cell
recognition properties, cell adhesivity, etc.,
which define a given developmental pathway. In the metathoracic pathway the gene
Rg-pbx would correspond to an activator,
the bithorax complex would represent the
selectors and a set of realisator genes, not
yet identified, would convert the bithorax
signal into those developmental characteristics that we see expressed in the behaviour of the proliferating metathoracic
cells. It is possible that the wildtype allele
of one of the loci absent in the Df(3)red is
involved in the normal synthesis of inductor molecules deposited in the cortex by the
maternal genome (Fig. 2).
HOMOEOTIC AND A l A V l C MUTATIONS IN INSECTS
PHYLOGENET1C AND ONTOGENETIC CONSIDERATIONS
The following considerations allow us to
| | sketch an operational model of how genes
may control and define developmental
pathways. If developmental pathways can
be considered as consisting of a sequence
of steps in a similar way to metabolic
pathways, sequential compartmentalization provides a material basis for these
steps (Garcia-Bellido, 1975a). Compartments are units of development affected,
as a whole, by the function of selector
genes. Compartments, within a given
imaginal disk, appear by binary partition
of a previously homogeneous cell population. At the moment of compartmentalization a selector gene is activated in one
compartment and repressed in its alternative one. Thus, at any stage of the development of a disk the mosaic distribution
of its compartments can be defined by the
specific combination of selectors at work in
these compartments. When a selector gene
that controls the developmental characteristics of a given compartment is mutated, development shifts into the pathway
characteristic of the alternative compartment. The additive effect of double mutants like bx and pbx, and en supports this conclusion. The mechansim of
segmentation of the embryo, however,
does not seem to occur by binary alternatives. Segments are apparently defined
simultaneously on the head, thorax and
abdomen. This may happen by the independent interpretation of cortical positional cues by nuclei populating the egg
cortex. It is therefore interesting to recall
that homoeotic mutations shift as a rule
the development of any particular segment in the direction of one thoracic segment, the mesothoracic one in Drosophila.
Thus it seems to be general that either
embryonic segments or compartments
within a disk result from the function of
selector genes that define developmental
pathways as binary alternatives (Fig. 1).
625
1949). In most cases the affected organs
(autotypes) have been considered as
phylogenetically more recent than the
mimicked one (telotype). Exceptions are
mutants that correspond to operator constitutive conditions (such as Cbx or Hm).
This conclusion can now be expressed in
genetic terms. During evolution, selector
genes have evolved which in the presence
of specific inductor molecules would act to
repress a primitive developmental pathway and thus permit the evolution of a new
developmental pathway to proceed. By
this evolutionary process homogeneity,
such as the sequential repetition of identical metameres is changed into diversity,
such as segments with specific characteristics of head, thorax and abdomen. When
these genes become inactive by mutation
the alternative (homoeotic) pathway that
appears is the thoracic one. It is therefore
assumed that the thoracic pathway is the
archetypic one. Similar considerations for
homoeotic mutations affecting the individual compartments of the appendages
suggest that the anterior, dorsal and proximal pathways are archetypes in the dorsal
appendages and their homologs in the
mesothoracic legs are the archetypes for
the ventral appendages (Garcia-Bellido,
1975a). It is in this sense that homoeotic
mutations can be considered as atavic,
since the archetype they uncover is presumably related to a phylogenetically more
primitive condition.
Developmental considerations seem to
support the same scheme. The transformations of appendages within dorsal and
within ventral series have an embryological
counterpart: Their anlagen are distributed
in segments maintaining a consistent
dorso-ventral location (Fig. 1). The recurrent transformation caused by homoeotic
mutants towards thoracic segments is
probably related to the location of the
"differentiation center" of Seidel, precisely
in this region of the blastoderm (see
Counce, 1973).
From these considerations several operThe study of homoeotic genes has been ational questions arise. The first is: Why
frequently associated with phylogenetic are selector genes expressed only in cerconsiderations (Bateson, 1894; Villee, tain segments or compartments? Coupled
1942; Goldschmidt, 1952; Herskowitz, with the function of these genes must be a
626
A. GARCIA-BELLIDO
mechanism that prevents its expression in
all places but one; or these genes are
exclusively activated there where they are
expressed. Probably the first possibility
prevails, i.e., their control seems to be
achieved by repression. As discussed above
there are indications in the bithorax complex that it is controlled by a negative
mechanism: it becomes activated in the
metathorax by the interaction of a gene
product (repressor) and an effector
molecule (inductor) differentially distributed in the cortex (positional cue) (Fig. 2).
We do not know by which mechanism the
selector genes remain activated during
subsequent development. But the possibility of DNA modification on the selector
locus or antirepressor functions of the
activated selector should be taken into consideration.
A second question is: How do selector
genes interact to define a given developmental pathway? It has been proposed that
their manifestation in developmental operations is mediated by the activation of
realisator genes. Since these realisator
genes are defining general morphogenetic
cell properties, most of them must be
ubiquitous and only a few would respond
to signals from one specific selector gene.
Thus, the characteristics of a developmental pathway probably result from the expression of a combination of realisator
genes controlled by a combination of selector genes. Several arguments suggest that
the control of realisator genes is also
achieved by a repression mechanism. This
model explains more easily 1) why the
maintenance of a developmental pathway
by a selector is coupled with the repression
of its alternative, for, in fact, the latter is a
consequence of the former; 2) why the
mutant condition of one or several selectors in the same pathway leads to an integrated transformation and not to a developmental chaos. The opposite is to be
expected from a positive type of control of
selectors upon selector-specific realisators;
and 3) how selection may have fixed new
selectors during evolution without the
need of creating a new set of integrated
realisator functions.
The uncontrolled function of genes de-
termining morphogenetic cell properties
would lead to random mitotic orientations,
constant mitotic rates, random distribution
of chaetes and trichomes, etc. We visualize
the appearance of developmental diversity
by the temporal and spatial repression, by
selectors, of that homogeneity. It is therefore interesting to note that the mesothoracic archetypes are more rich in pattern
elements and these more randomly distributed than the new autotypes. Thus, selector interaction, assumed to occur in the
combinatorial control of developmental
pathways, may result from independent
repression of some realisators in that particular pathway. The non-repressed
realisators will so define the developmental
characteristic of that pathway (Fig. 3). And
yet, at least one cell behaviour property
characteristic of selectors seems to escape
this negative control: it is the property of
specific cell recognition. The cell surface
label typical of the cells of a given compartment must be a new quality and therefore either it is synthesized by a realisator
gene under positive control or is the product of the selector gene itself.
The proposed model predicts that 1) the
archetypic pathways will have more
realisator functions than the autotypic
ones; 2) the archetypes will require no
selector genes to control them. It is hoped
that molecular and genetic analysis will
soon put these predictions to test.
The data obtained from some homoeotic mutants ("disruptive" ones), regenerative homoeosis and from transdetermination studies seem to be in line with these
propositions. Disruptive mutations whose
primary effects are to accumulate unwanted metabolic products may lead to cell
lethality and extra proliferation in situ.
Similarly, culture of fragments of imaginal
disks can upset the fine tuning of control
of cell behaviour and so lead to repression
of selector genes. It is a possible consequence of this that pathways return to the
archetypic condition. The conservativeness of transformations to members of the
same series, or the final irreversible transformation to dorsal mesothoracic notum in
transdetermination could be explained in
these terms.
627
HOMOEOTIC AND ATAV1C MUTATIONS IN INSECTS
COMPARTMENTS
12 4 7 8 9
12 4 7 89
DEVELOPMENTAL
PATHWAVS
12 4 7 89
.
, 1 2
7
9
1
4 7
1 2
7
1
1
I
I
9
12 4 7 8 9
1 2 4
8 9
1
4 7
1
4
1 2
7
9
1 2
ft'
LEVEL OF ACTION
Realisators
Homoeotic
Mutations
Selectors
Phenocopies
Transdetermination
Activators
FIG. 3. Genetic control of a developmental pathway
by the combinatorial effect of three regulatory steps.
Same symbolism as in Figure 2. Arabic numbers:
realisator genes. Those expressed in the different
developmental pathways define those pathways. The
non-expressed ones correspond to the ones repressed
by the corresponding selector genes (a, /? and -y). A, B
and G are activator genes whose repressor prducts
are inactive because of inactivation by i", i" and iT
inductor molecules. Further explanations in text.
Indeed, the preceeding considerations
and the postulated model are largely
speculative. However, since the elements
involved in the model are susceptible to
genetic analysis, the study of available and
newly isolated mutants and their interactions will help to test it.
(Russian with English summary). Genetika 4:5864.
Baker, W. K. 1977. A clonal basis for early developmental restrictions in the head of Drosophila. Devel.
Biol. (In press)
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