Nature has evolved an astonishing variety of genetic and epigenetic sex-determining systems which all achieve the same result, the generation of two sexes. Genetic and molecular analyses, mainly performed during the last 20 years, have gradually revealed the mechanisms that govern sexual differentiation in a few model organisms. In this review, we will introduce the sex-determining system of Drosophila and compare the fruitfly to the housefly Musca domestica and other Dipteran insects. Despite the ostensible variety, all these insects use the same basic strategy: a primary genetic signal that is different in males and females, a key gene that responds to the primary signal, and a double-switch gene that eventually selects between two alternative sexual programmes. These parallels, however, do not extend to the molecular level. Except for the double-switch gene doublesex at the end of the cascade, no functional homologies were found between more distantly related insects. In particular, Sex-lethal, the key gene that controls sexual differentiation in Drosophila, does not have a sex-determining function in any other genus studied so far. These results show that sex-determining cascades, in comparison to other regulatory pathways, evolve much more rapidly.

REFERENCES

Albrecht
E. B.
,
Salz
H. K.
(
1993
)
The Drosophila sex determination gene snf is utilized for the establishment of the female-specific splicing pattern of Sex-lethal.
Genetics
134
,
801
807
Amrein
H.
,
Gorman
M.
,
Nöthiger
R.
(
1988
)
The sex-determining gene tra-2 of Drosophila encodes a putative RNA binding protein.
Cell
55
,
1025
1035
An
W.
,
Wensink
P. C.
(
1995
)
Integrating sex-and tissue-specific regulation within a single Drosophila enhancer.
Genes Dev
9
,
256
266
Baker
B. S.
,
Ridge
K. A.
(
1980
)
Sex and the single cell. On the action of major loci affecting sex determination in Drosophila melanogaster.
Genetics
94
,
383
423
Barbash
D. A.
,
Cline
T. W.
(
1995
)
Genetic and molecular analysis of the autosomal component of the primary sex determination signal of Drosophila melanogaster.
Genetics
141
,
1451
1471
Bashaw
G. J.
,
Baker
B. S.
(
1995
)
The msl-2 dosage compensation gene of Drosophila encodes a putative DNA-binding protein whose expression is sex-specifically regulated by Sex-lethal.
Development
121
,
3245
3258
Bashaw
G. J.
,
Baker
B. S.
(
1997
)
The regulation of the Drosophilamsl-2 gene reveals a function for Sex-lethal in translational control.
Cell
89
,
789
798
Bell
L. R.
,
Maine
E. M.
,
Schedl
P.
,
Cline
T. W.
(
1988
)
Sex-lethal, a Drosophila sex determination switch gene, exhibits sex-specific RNA splicing and sequence similarity to RNA binding proteins.
Cell
55
,
1037
1046
Bell
L. R.
,
Horabin
J. I.
,
Schedl
P.
,
Cline
T. W.
(
1991
)
Positive autoregulation of Sex-lethal by alternative splicing maintains the female determined state in Drosophila.
Cell
65
,
229
239
Belote
J. M.
,
Baker
B. S.
(
1982
)
Sex determination in Drosophila melanogaster: Analysis of transformer-2, a sex-transforming locus.
Proc. Natl. Acad. Sci. USA
79
,
1568
1572
Belote
J. M.
,
Handler
A. M.
,
Wolfner
M. F.
,
Livak
K. L.
,
Baker
B. S.
(
1985
)
Sex specific regulation of yolk protein gene expression in Drosophila.
Cell
40
,
339
348
Bernstein
M.
,
Cline
T. W.
(
1994
)
Differential effects of Sex-lethal mutations on dosage compensation early in Drosophila development.
Genetics
136
,
1051
1061
Bone
J. R.
,
Lavender
J.
,
Richman
R.
,
Palmer
M. J.
,
Turner
B. M.
,
Kuroda
M. I.
(
1994
)
Acetylated histone H4 on the male X chromosome is associated with dosage compensation in Drosophila.
Genes Dev
8
,
96
104
Bopp
D.
,
Bell
L. R.
,
Cline
T. W.
,
Schedl
P.
(
1991
)
Developmental distribution of female-specific Sex-lethal proteins in Drosophila melanogaster.
Genes Dev
5
,
403
415
Bopp
D.
,
Horabin
J. I.
,
Lersch
R. A.
,
Cline
T. W.
,
Schedl
P.
(
1993
)
Expression of the Sex-lethal gene is controlled at multiple levels during Drosophila oogenesis.
Development
118
,
797
812
Bopp
D.
,
Calhoun
G.
,
Horabin
J. I.
,
Samuels
M.
,
Schedl
P.
(
1996
)
Sex-specific control of Sex-lethal is a conserved mechanism for sex determination in the genus Drosophila.
Development
122
,
971
982
Bopp
D.
,
Schutt
C.
,
Puro
J.
,
Huang
H.
,
Nöthiger
R.
(
1999
)
Recombination and disjunction in female germ cells of Drosophila depend on the germline activity of the gene Sex-lethal.
Development
126
,
5785
5794
Bownes
M.
,
Steinmann-Zwicky
M.
,
Nöthiger
R.
(
1990
)
Differential control of yolk protein gene expression in fat bodies and gonads by the sex-determining gene tra-2 of Drosophila.
EMBO J
9
,
3975
3980
Burtis
K. C.
,
Baker
B. S.
(
1989
)
Drosophiladoublesex gene controls somatic sexual differentiation by producing alternatively spliced mRNAs encoding related sex-specific polypeptides.
Cell
56
,
997
1010
Cabrera
C. V.
,
Alonso
M. C.
(
1991
)
Transcriptional activation by heterodimers of the achaete-scute and daughterless gene products of Drosophila.
EMBO J
10
,
2965
2973
Chandler
D.
,
McGuffin
M. E.
,
Piskur
J.
,
Yao
J.
,
Baker
B. S.
,
Mattox
W.
(
1997
)
Evolutionary conservation of regulatory strategies for the sex determination factor transformer-2.
Mol. Cell. Biol
17
,
2908
2919
Chase
B. A.
,
Baker
B. S.
(
1995
)
A genetic analysis of intersex, a gene regulating sexual differeniation in Drosophila melanogaster females.
Genetics
139
,
1649
1661
Cho
S.
,
Wensink
P. C.
(
1997
)
DNA binding by the male and female doublesex proteins of Drosophila melanogaster.
J. Biol. Chem
272
,
3185
3189
Cho
S.
,
Wensink
P. C.
(
1998
)
Linkage between oligomerization and DNA binding in Drosophiladoublesex proteins.
Biochemistry
37
,
11301
11308
Cline
T. W.
(
1988
)
Evidence that sisterless-a and sisterless-b are two of several discrete “numerator elements” of the X/A sex determination signal in Drosophila that switch Sxl between two alternative stable expression states.
Genetics
119
,
829
862
Cline
T. W.
(
1993
)
The Drosophila sex determination signal: how do flies count to two?.
Trends Genet
9
,
385
390
Cline
T. W.
,
Meyer
B. J.
(
1996
)
Vive la difference: males vs females in flies vs worms.
Annu. Rev. Genet
30
,
637
702
Coschigano
K. T.
,
Wensink
P. C.
(
1993
)
Sex-specific transcriptional regulation by the male and female doublesex proteins of Drosophila.
Genes Dev
7
,
42
54
Cronmiller
C.
,
Schedl
P.
,
Cline
T. W.
(
1988
)
Molecular characterization of daughterless, a Drosophila sex determination gene with multiple roles in development.
Genes Dev
2
,
1666
1676
Dauwalder
B.
,
Amaya-Manzanares
F.
,
Mattox
W.
(
1996
)
A human homologue of the Drosophila sex determination factor transformer-2 has conserved splicing regulatory functions.
Proc. Natl. Acad. Sci. USA
93
,
9004
9009
Deshpande
G.
,
Stukey
J.
,
Schedl
P.
(
1995
)
scute (sis-b) function in Drosophila sex determination.
Mol. Cell Biol
15
,
4430
4440
Deshpande
G.
,
Samuels
M. E.
,
Schedl
P.
(
1996
)
Sex-lethal interacts with splicing factors in vitro and in vivo.
Mol. Cell Biol
16
,
5036
5047
Duffy
J. B.
,
Gergen
J. P.
(
1991
)
The Drosophila segmentation gene runt acts as a position-specific numerator element necessary for the uniform expression of the sex-determining gene Sex-lethal.
Genes Dev
5
,
2176
2187
Erickson
J. W.
,
Cline
T. W.
(
1993
)
A bZIP protein, sisterless-a, collaborates with bHLH transcription factors early in Drosophila development to determine sex.
Genes Dev
7
,
1688
1702
Estes
P. A.
,
Keyes
L. N.
,
Schedl
P.
(
1995
)
Multiple response elements in the Sex-lethal early promoter ensure its female-specific expression pattern.
Mol. Cell. Biol
15
,
904
917
Finley
K. D.
,
Taylor
B. J.
,
Milstein
M.
,
McKeown
M.
(
1997
)
dissatisfaction, a gene involved in sex-specific behavior and neural development of Drosophila.
Genetics
94
,
913
918
Flickinger
T. W.
,
Salz
H. K.
(
1994
)
The Drosophila sex determination gene snf encodes a nuclear protein with sequence and functional similarity to the mammalian U1A snRNP protein.
Genes Dev
8
,
914
925
Granadino
B.
,
Juán
A. S.
,
Santamaria
P.
,
Sánchez
L.
(
1992
)
Evidence of a dual function in fl(2)d, a gene needed for Sex-lethal expression in Drosophila melanogaster.
Genetics
130
,
597
612
Hager
J. H.
,
Cline
T. W.
(
1997
)
Induction of female Sex-lethal RNA splicing in male germ cells: implications for Drosophila germline sex determination.
Development
124
,
5033
5048
Hilfiker
A.
,
Amrein
H.
,
Dubendorfer
A.
,
Schneiter
R.
,
Nöthiger
R.
(
1995
)
The gene virilizer is required for female-specific splicing controlled by Sxl, the master gene for sexual development in Drosophila.
Development
121
,
4017
4026
Hilfiker-Kleiner
D.
,
Dubendorfer
A.
,
Hilfiker
A.
,
Nöthiger
R.
(
1994
)
Genetic control of sex determination in the germ line and soma of the housefly, Musca domestica.
Development
120
,
2531
2538
Hinson
S.
,
Nagoshi
R. N.
(
1999
)
Regulatory and functional interactions between the somatic sex regulatory gene transformer and the germline genes ovo and ovarian tumor.
Development
126
,
861
871
Hodgkin
J.
(
1990
)
Sex determination compared in Drosophila and Caenorhabditis.
Nature
344
,
721
728
Horabin
J. I.
,
Schedl
P.
(
1993
)
Regulated splicing of the Drosophila Sex-lethal male exon involves a blockage mechanism.
Mol. Cell. Biol
13
,
1408
1414
Hoshijima
K.
,
Inoue
K.
,
Higuchi
I.
,
Sakamoto
H.
,
Shimura
Y.
(
1991
)
Control of doublesex alternative splicing by transformer and transformer-2 in Drosophila.
Science
252
,
833
836
Hoshijima
K.
,
Kohyama
A.
,
Watakabe
I.
,
Inoue
K.
,
Sakamoto
H.
,
Shimura
Y.
(
1995
)
Transcriptional regulation of the Sex-lethal gene by helix-loop-helix proteins.
Nucleic Acids Res
23
,
3441
3448
Kelley
R. L.
,
Solovyeva
I.
,
Lyman
L. M.
,
Richman
R.
,
Solovyev
V.
,
Kuroda
M. I.
(
1995
)
Expression of msl-2 causes assembly of dosage compensation regulators on the X chromosomes and female lethality in Drosophila.
Cell
81
,
867
877
Kelley
R. L.
,
Wang
J.
,
Bell
L.
,
Kuroda
M. I.
(
1997
)
Sex lethal controls dosage compensation in Drosophila by a non-splicing mechanism.
Nature
387
,
195
199
Keyes
L. N.
,
Cline
T. W.
,
Schedl
P.
(
1992
)
The primary sex determination signal of Drosophila acts at the level of transcription.
Cell
68
,
933
943
Kramer
S. G.
,
Timothy
M. J.
,
Schedl
P.
,
Gergen
J. P.
(
1999
)
Direct activation of Sex-lethal transcription by the Drosophila Runt protein.
Development
126
,
191
200
Lopez
A. J.
(
1998
)
Alternative splicing of pre-mRNA: Developmental consequences and mechanisms of regulation.
Annu. Rev. Genet
32
,
279
305
Loukeris
T. G.
,
Livadaras
I.
,
Arcà
B.
,
Zabalou
S.
,
Savakis
C.
(
1995
)
Gene transfer into the Medfly, Ceratitis capitata with a Drosophilahydei transposable element.
Science
270
,
2002
2005
Lucchesi
J. C.
(
1996
)
Dosage compensation in Drosophila and the ‘complex’ world of transcriptional regulation.
BioEssays
18
,
541
547
Marín
I.
,
Baker
B. S.
(
1998
)
The evolutionary dynamics of sex determination.
Science
281
,
1990
1994
Meise
M.
,
Hilfiker-Kleiner
D.
,
Dubendorfer
A.
,
Brunner
C.
,
Nöthiger
R.
,
Bopp
D.
(
1998
)
Sex-lethal, the master sex-determining gene in Drosophila, is not sex-specifically regulated in Musca domestica.
Development
125
,
1487
1494
Misquitta
L.
,
Paterson
B. M.
(
1999
)
Targeted disruption of gene function in Drosophila by RNA interference (RNA-i): A role for nautilus in embryonic somatic muscle formation.
Proc. Natl. Acad. Sci. USA
96
,
1451
1456
Mori
L.
,
Perondini
A. L. P.
(
1980
)
Errors in the elimination of X chromosomes in Sciara ocellaris.
Genetics
94
,
663
673
Muller-Holtkamp
F.
(
1995
)
The Sex-lethal gene homologue in Chrysomya rufifacies is highly conserved in sequence and exon-intron organization.
J. Mol. Evol
41
,
467
477
Nöthiger
R.
,
Steinmann-Zwicky
M.
(
1985
)
Sex determination in Drosophila.
Trends Genet
1
,
209
215
Nöthiger
R.
,
Steinmann-Zwicky
M.
(
1992
)
Genetic control of sex determination.
Semin. Dev. Biol.
3
Oliver
B.
,
Kim
Y.-J.
,
Baker
B. S.
(
1993
).
Sex-lethal, master and slave: a hierarchy of germ-line sex determination in Drosophila.
Development
119
,
897
908
O'Neil
M. T.
,
Belote
J. M.
(
1992
)
Interspecific comparison of the transformer gene of Drosophila reveals an unusually high degree of evolutionary divergence.
Genetics
131
,
113
128
Parkhurst
S. M.
,
Bopp
D.
,
Ish-Horowicz
D.
(
1990
)
X:A ratio, the primary sex-determining signal in Drosophila, is transduced by helix-loop-helix proteins.
Cell
63
,
1179
1191
Parkhurst
S. M.
,
Ish-Horowicz
D.
(
1992
)
Common denominators for sex.
Curr. Biol
2
,
629
631
Paroush
Z.
,
Finley
R. L.
,
Kidd
T.
,
Wainwright
S. M.
,
Ingham
P. W.
,
Brent
R.
,
Ish-Horowicz
D.
(
1994
)
groucho is required for Drosophila neurogenesis, segmentation, and sex determination and interacts directly with hairy -related bHLH proteins.
Cell
79
,
805
815
Pauli
D.
,
Oliver
B.
,
Mahowald
A. P.
(
1993
)
The role of the ovarian tumor locus in Drosophila melanogaster germ line sex determination.
Development
119
,
123
134
Pultz
M. A.
,
Carson
G. S.
,
Baker
B. S.
(
1994
)
A genetic analysis of hermaphrodite, a pleiotropic sex determination gene in Drosophila melanogaster.
Genetics
136
,
195
207
Pultz
M. A.
,
Baker
B. S.
(
1995
)
The dual role of hermaphrodite in the Drosophila sex determination regulatory hierarchy.
Development
121
,
99
111
Raymond
C. S.
,
Shamu
C. E.
,
Shen
M. M.
,
Seifert
K. J.
,
Hirsch
B.
,
Hodgkin
J.
,
Zarkower
D.
(
1998
)
Evidence for evolutionary conservation of sex-determining genes.
Nature
391
,
691
695
Ryner
L. C.
,
Goodwin
S. F.
,
Castrillon
D. H.
,
Anand
A.
,
Villella
A.
,
Baker
B. S.
,
Hall
J. C.
,
Taylor
B. J.
,
Wasserman
S. A.
(
1996
)
Control of male sexual behavior and sexual orientation in Drosophila by the fruitless gene.
Cell
87
,
1079
1089
Saccone
G.
,
Pelusio
I.
,
Artiaco
D.
,
Giordano
E.
,
Bopp
D.
,
Polito
L. C.
(
1998
)
The Ceratitis capitata homologue of the Drosophila sex-determining gene Sex-lethal is structurally conserved, but not sex-specifically regulated.
Development
125
,
1495
1500
Salz
H. K.
(
1992
)
The genetic analysis of snf: a Drosophila sex determination gene required for activation of Sex-lethal in both the germline and the soma.
Genetics
130
,
547
554
Schmidt
R.
,
Hediger
M.
,
Nöthiger
R.
,
Dubendorfer
A.
(
1997
)
The mutation masculinizer (man) defines a sex-determining gene with maternal and zygotic functions in Musca domestica L.
Genetics
145
,
173
183
Schupbach
T.
(
1985
)
Normal female germ cell differentiation requires the female X chromosome to autosome ratio and expression of Sex-lethal in Drosophila melanogaster.
Genetics
109
,
529
548
Schutt
C.
,
Hilfiker
A.
,
Nöthiger
R.
(
1998
)
virilizer regulates Sex-lethal in the germline of Drosophila melanogaster.
Development
125
,
1501
1507
Shearman
D. C. A.
,
Frommer
M.
(
1998
)
The Bactrocera tryoni homologue of the Drosophila melanogaster sex-determination gene doublesex.
Insect Mol. Biol
7
,
1
12
Sievert
V.
,
Kuhn
S.
,
Traut
W.
(
1997
)
Expression of the sex-determining cascade genes Sex-lethal and doublesex in the phorid fly Megaselia scalaris.
Genome
40
,
211
214
Sosnowski
B. A.
,
Belote
J. M.
,
McKeown
M.
(
1989
)
Sex-specific alternative splicing of RNA from the transformer gene results from sequence-dependent splice site blockage.
Cell
58
,
449
459
Staab
S.
,
Heller
A.
,
Steinmann-Zwicky
M.
(
1996
)
Somatic sex-determining signals act on XX germ cells in Drosophila embryos.
Development
122
,
4065
4071
Steinmann-Zwicky
M.
,
Schmid
H.
,
Nöthiger
R.
(
1989
)
Cell-autonomous and inductive signals can determine the sex of the germ line of Drosophila by regulating the gene Sxl.
Cell
57
,
157
166
Steinmann-Zwicky
M.
(
1993
)
Sex determination in Drosophila: sis-b, a major numerator element of the X:A ratio in the soma, does not contribute to the X:A ratio in the germ line.
Development
117
,
763
767
Steinmann-Zwicky
M.
(
1994
)
Sxl in the germline of Drosophila: a target for somatic late induction.
Dev. Genet
15
,
265
274
Taylor
B. J.
,
Villella
A.
,
Ryner
L. C.
,
Baker
B. S.
,
Hall
J. C.
(
1994
)
Behavioral and neurobiological implications of sex-determining factors in Drosophila.
Dev. Genet
15
,
275
296
Ullerich
F.-H.
(
1984
)
Analysis of sex determination in the monogenic blowfly Chrysomya rufifacies by pole cell transplantation.
Mol. Gen. Genet
193
,
479
487
Van Doren
M.
,
Ellis
H. M.
,
Posakony
J. W.
(
1991
)
The Drosophila extramacrochaetae protein antagonizes sequence-specific DNA binding by daughterless/achaete-scute protein complexes.
Development
113
,
245
255
Wilkins
A. S.
(
1995
)
Moving up the hierarchy: A hypothesis on the evolution of a genetic sex determination pathway.
BioEssays
17
,
71
77
Yi
W.
,
Zarkower
D.
(
1999
)
Similarity of DNA binding and transcriptional regulation by Caenorhabditis elegans MAB-3 and Drosophila melanogaster DSX suggests conservation of sex determining mechanisms.
Development
126
,
873
881
Younger-Shepherd
S.
,
Vaessin
H.
,
Bier
E.
,
Jan
L. Y.
,
Jan
Y. N.
(
1992
)
deadpan, an essential pan-neural gene encoding an HLH protein, acts as a denominator in Drosophila sex determination.
Cell
70
,
911
922
Zhou
S.
,
Yang
Y.
,
Scott
M. J.
,
Eisen
A.
,
Koonin
E. V.
,
Fouts
D. L.
,
Wrightsman
R.
,
Manning
J. E.
,
Lucchesi
J. C.
(
1995
)
Male-specific lethal 2, a dosage compensation gene of Drosophila, undergoes sex-specific regulation and encodes a protein with a RING finger and a metallothionein-like cystein cluster.
EMBO J
14
,
2884
2895
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