A cluster of
Drosophila
homeobox genes
involved in mesoderm differentiation
programs
Krzysztof Jagla,
1
Maria Bellard,
2
and Manfred Frasch
3
*
Summary
Although genes involved in common developmental
programs are usually scattered throughout the metazoan
genome, there are some important examples of function-
ally interconnected regulatory genes that display close
physical linkage. In particular the homeotic genes, which
determine the identities of body parts, are clustered in
the Hox complexes and clustering is thought to be crucial
for the proper execution of their developmental pro-
grams. Here we describe the organization and functional
properties of a more recently identified cluster of six
homeobox genes at 93DE on the third chromosome of
Drosophila
. These genes, which include
tinman
,
bagpipe
,
ladybird early
,
ladybird late
,
C15
, and
slouch
, all partici-
pate in mesodermal patterning and differentiation pro-
grams and show multiple regulatory interactions among
each other. We propose that their clustering, through
unknown mechanisms, is functionally significant and
discuss the similarities and differences between the
93DE homeobox gene cluster and the Hox complexes.
BioEssays 23:125±133, 2001.
ß 2001 John Wiley & Sons, Inc.
Introduction
Homeobox-containing genes code for transcription factors
with DNA-binding domains that are highly conserved in terms
of their primary sequence and helix-turn-helix structure.
(1)
On
the basis of sequence similarities, these genes have been
further divided into several families and subfamilies. Function-
ally, homeobox-containing genes have been implicated in a
large variety of regulatory events during animal development.
In general, homeobox genes are distributed throughout the
genome as individual genes or gene pairs, but interestingly,
some of them are organized in clusters.
(2,3)
Genetic studies by E.B. Lewis in Drosophila uncovered the
first example of a complex of homeotic selector genes. This
complex controls segmental identities and was termed Bitho-
rax Complex (Bx-C).
(4,5)
Bx-C and the subsequently identified
Antennapedia Complex (Antp-C)
(6)
represent a bipartite
homeotic gene complex, which is now known to include a
total of eight homeoboxgenes representing classical homeotic
genes and four additional homeobox genes with other fun-
ctions. In addition to Drosophila, single or multiple clusters of
homeotic genes with a highly conserved organization have
been discovered in many different animal species.
(7±9)
The
multiplicity of mammalian Hox clusters is thought to result from
a two-step mechanism of gene duplications, and may explain
the phylogenetic link between Drosophila and mammalian
homeotic clusters.
(8,10)
According to this hypothesis, a cluster
was initially formed by tandem gene duplications and
resembles the common ancestor for Hox complexes of
both invertebrates and vertebrates.
(7,9)
The subsequent gene-
ration of multiple Hox complexes in the vertebrate lineage
appears to be a result of one or two genome duplications. It
is significant that, in spite of multiple types of genomic
rearrangements, such as splitting and partial inversion
(Drosophila), duplication and loss or gain of genes (mammals,
zebrafish), homeotic gene clustering was strictly maintained
during evolution.
A number of common structural and functional features of
the Hox gene clusters attest to the universality of basic
mechanisms underlying body plan formation. These include:
(1) ``Spatial colinearity'', the correlation between the order of
genes on the chromosome and their (partially overlapping)
expression domains along the anteroposterior (AP) axis of the
BioEssays 23:125±133, ß 2001 John Wiley & Sons, Inc. BioEssays 23.2 125
1
INSERM U.384, Clermont Ferrand Cedex, France.
2
Institut de Ge
Â
ne
Â
tique et de Biologie Mole
Â
culaire et Cellulaire, Illkirch
Cedex, France.
3
Mount Sinai School of Medicine, Department for Biochemistry and
Molecular Biology.
Correspondence to: Dr. Manfred Frasch, Mount Sinai School of
Medicine, Department for Biochemistry and Molecular Biology, Box
1020, One Gustave L. Levy Place, New York, NY 10029.
E-mail: Manfred.frasch@mssm.edu
Abbreviations: Bx-C, Bithorax Complex; Antp-C, Antennapedia Com-
plex; bap, bagpipe; CNS, central nervous system; DM cells, dorsal
median cells; Dfd, Deformed; Dpp, Decapentaplegic protein; eh1,
Engrailed homology domain 1; En, Engrailed protein; ftz, fushi tarazu;
hh, hedgehog; Hox-C, homeotic gene complex; inr, insulin receptor
gene; LaP, lateral adult muscle precursor; lbe, ladybird-early; lbl,
ladybird-late; mef-2, myocyte enhancer factor-2 gene; NK, Nirenberg-
Kim; slou, slouch; tin, tinman; TN, Tinman N-terminal homology
domain; vnd, ventral nervous system defective; SBM, segment border
muscle; scrou, scarecrow; wg, wingless.
Review articles