Transcript HOX genes (1)

Homeotic genes in Drosophila
body patterning
Genetics Unit, Department of Biochemistry
[email protected]
Developmental biology:
Drosophila segmentation and repeated units
* egg: generate the system
* larva: eat and grow
* pupa: structures in
larvae grow out to form
adult fly: metamorphosis
(Drosophila is a
holometabolous insect)
1
Homeotic gene complexes in
Drosophila
• ANT-C
(Antennapedia
complex)
is
largely
responsible for segmental
identity in the head and
anterior thorax.
• BX-C (Bithorax complex)
is
responsible
for
segmental identity in the
posterior
thorax
and
abdomen.
HOMEOSIS
• Homeosis or homeotic transformation, is
the development of one body part with the
phenotype of another.
The bithorax mutations
• This class of loss of
functions
mutations
cause the entire third
thoracic segment to be
transformed into a
second
thoracic
segment giving rise to
flies with four wings
instead for the normal
two.
The Tab dominant mutations
• These gain of function
mutations transform
part of the second
thoracic segment into
the sixth abdominal
segment.
The Antennapedia mutations
• These gain of function mutations
transform antenna into leg.
The Homeodomain
• The homeotic genes encode transcription
factors of a class called homeodomain
proteins. The homeodomain is a 60aa
protein domain, which binds DNA. Hox
genes bind DNA regulatory elements of
their target genes in a specific combination
so that the expression pattern in each of the
different segments is unique.
The mystery of the homeodomain
specificity
• In vitro, homeodomains
have a very broad binding
specificity, which does not
explain the refined
specific regulation of
target genes observed in
vivo. So how can this be
explained?
The co-linearity principle: Homeotic gene expression in Drosophila
• The anterior boundary of homeotic gene expression is ordered from
SCR (most anterior to ANTP, UBX and ABD-B (most posterior).
This order is matched by the linear arrangement of the
corresponding genes along chromosome 3.
Mechanisms underlying
functional diversity of Hox
proteins
Understanding how function is encoded
within Hox protein structure
The co-factor hypothesis
• There is the possibility of
specific co-factors, which
are expressed in the
domain of expression of
the Hox-gene. Until now
very few were found, the
most prominent example
being Extradenticle and
Homothorax (EXD, HTH;
Ryoo et al, Development
126, pp 5137-48, 1999).
Dll repression:
a paradigm for the study of Hox/Exd interaction
T
1
Gebelein et al, Dev. Cell, 2002
T2
DME-lacZ / Ubx
T3
A1
A2
Ubx
Exd
AbdA +
Dll
The DNA sequence motif
hypothesis
• Different combination of
DNA modules would give
different combination of
co-factors bound on the
promoter and thus a
different
array
of
transcriptional interactions
with each Hox protein (Li
et al, Development 126,
5581-5589, 1999).
Insect vs. mammalian Hox genes
Expression patterns of mouse
Hox genes
Phenotype of a homeotic mutant mouse
• Mice mutant for a
targeted knockout of
the HoxC8 gene reveal
ribs duplication and a
clenched-fingers
phenotype.
Developmental
strategies
in
animals are ancient and highly
conserved. In essence, a mammal, a
worm and a fly-three very different
organisms-are put together with the
same basic building blocks and
regulatory devices.
Is there a “ground” state?
Changes in Hox gene expression can
help explain the evolution of
arthropod body plans
Wild type
Hox mutant
Lewis et al. 2000
Averof and Patel 1997 Nature 388, 682-686
Averof 2002 Curr Op Genetics and Development
1386-392
Averof and Patel 1997
Expression of Hox genes in arthropods
crustaceans
Branchiopoda
(Artemia, the brine-shrimp)
Malacostracans
(Lobsters, hermit crabs)
Insects
Evolution of crustacean maxillipeds
species 1
species 2
Triops (no mxp): Ubx expression in all thoracic segments
Mysid (1 mxp): Ubx expression from T2 to the posterior
T1
T1
T2
T2
T3
T3
Reading List
Textbooks: 1). Scott F Gilbert (2003).
Developmental Biology 7th edition, chapter
9, pp285-290; 2). Wolpert Evolution and
development chapter in Principles of
development
General review: McGinnis W and
Krumlauf R (1992). Homeobox genes and
axial patterning Cell, 68, pp283-302.
Evolution of body pattern review: Averof
M (2002) Curr Op Genetics and
Development 1386-392