Download ab.homeobox genes

HOMEOBOX GENES
From Drosophila melanogaster
to pathogenesis of congenital malformations
in Homo sapiens
Olga Haus
Homeotic genes
of Drosophila melanogaster (fruit fly)
hom
Genes, which mutations cause
the segments of one part of the organism
becoming similar
to the segments of its another part
(homeo = I become similar)
Homeotic mutations
Mutations, by which one developmental
scheme becomes replaced by another
They cause abnormal differentiation of organs
or
the development of organs
typical for adjacent segment
Dictionary of Genetics, King & Stansfield,2002
Homeotic transformation (mutation)
1. Loss of function: one homeotic gene loses
its activity in a given segment, so another
hom takes over the control of this
segment  the development of structures
characteristic for another segment
2. Activating: homeotic gene, activated in a
segment which normally is not directed by
it, takes over the control on this segment
HOMEOBOX GENES
I class – HOX/Hox genes – localized in
complexes (clusters: A,B,C,D) (eg. HOXA9,
HOXB3)
II class – non-HOX/Hox genes – localized
beyond four main clusters (eg. HOX11)
HOMEOBOX GENES
molecular architects
• determine spatial localizations of the cells in
different parts of the organism along anterior –
posterior axis
• exist in DNA of all cells, but their expression
occur only in these, which are localized in the
segments directed by a given gene
• in a given tissue (organ) – specific constellation
(configuration) of expression of different Hox
genes
HOMEOBOX GENES
molecular architects
• determine spatial localizations of the cells in
different parts of the organism along anterior –
posterior axis
• exist in DNA of all cells, but their expression
occur only in these, which are localized in the
segments directed by a given gene
• in a given tissue (organ) – specific constellation
(configuration) of expression of different Hox
genes
HOMEOBOX GENES
molecular architects
• determine spatial localizations of the cells in
different parts of the organism along anterior –
posterior axis
• exist in DNA of all cells, but their expression
occur only in these, which are localized in the
segments directed by a given gene
• in a given tissue (organ) – specific constellation
(configuration) of expression of different Hox
genes
HOMEOBOX
homeotic sequence (180 nucleotides)
• decides about the specificity (function) of a gene
• codes for a homeotic domain (60 aminoacids),
responsible for DNA-linking
• conserved in evolution process from a common
ancestor of Drosophila (hom), mouse (Hox) and
man (HOX)
• beside homeodomain the HOX proteins of different
species are different
HOMEOBOX
homeotic sequence (180 nucleotides)
• decides about the specificity (function) of a gene
• codes for a homeotic domain (60 aminoacids),
responsible for DNA-linking
• conserved in evolution process from a common
ancestor of Drosophila (hom), mouse (Hox) and
man (HOX)
• beside homeodomain the HOX proteins of different
species are different
HOMEOBOX
homeotic sequence (180 nucleotides)
• decides about the specificity (function) of a gene
• codes for a homeotic domain (60 aminoacids),
responsible for DNA-linking
• conserved in evolution process from a common
ancestor of Drosophila (hom), mouse (Hox) and
man (HOX)
• beside homeodomain the HOX proteins of different
species are different
HOMEOBOX
homeotic sequence (180 nucleotides)
• decides about the specificity (function) of a gene
• codes for a homeotic domain (60 aminoacids),
responsible for DNA-linking
• conserved in evolution process from a common
ancestor of Drosophila (hom), mouse (Hox) and
man (HOX)
• beside homeodomain the HOX proteins of different
species are different
HOX genes in humans
• 38 genes
• 4 clusters (A,B,C,D) – the result of double
duplication of the primordial 13-genes complex
• gradual loss of genes during the evolution  no
cluster consists of all 13 genes of primordial
complex
• localization - chromosomes: 2, 7, 12, 17
• paralogic (orthologic) genes – localized in the same
sites (loci) of different complexes
HOX genes in humans
• 38 genes
• 4 clusters (A,B,C,D) – the result of double
duplication of the primordial 13-genes complex
• gradual loss of genes during the evolution  no
cluster consists of all 13 genes of primordial
complex
• localization - chromosomes: 2, 7, 12, 17
• paralogic (orthologic) genes – localized in the same
sites (loci) of different complexes
HOX genes in humans
• 38 genes
• 4 clusters (A,B,C,D) – the result of double
duplication of the primordial 13-genes complex
• gradual loss of genes during the evolution  no
cluster consists of all 13 genes of primordial
complex
• localization - chromosomes: 2, 7, 12, 17
• paralogic (orthologic) genes – localized in the same
sites (loci) of different complexes
HOX genes in humans
• 38 genes
• 4 clusters (A,B,C,D) – the result of double
duplication of the primordial 13-genes complex
• gradual loss of genes during the evolution  no
cluster consists of all 13 genes of primordial
complex
• localization - chromosomes: 2, 7, 12, 17
• paralogic (orthologic) genes – localized in the same
sites (loci) of different complexes
LINEAR ORDER OF HOX GENES
of a complex (from 3’ to 5’)
REFLECTS:
• the order (succession) of body regions directed
by them along antero-posterior axis
• the order of their activation and expression in
embryo
• the degree of their susceptibility to retinoid acid
LINEAR ORDER OF GENES
analogical in different species of animals
genes in the same loci of different complexes in
different animal species (paralogic genes):
• more similar, structurally and functionally, than
successive (next) genes in a given complex
• originate from a common gene ancestor
• may replace each other between the species
Controlled homeotic mutations in mice
pathology of mice fetuses and mature
individuals
comparison with a phenotype of congenital
malformation in humans
search for adequate (homologic, paralogic)
HOX gene in humans
The enigma of HOXA3
controlled HoxA3 mutation in mice (Capecchi
1994) 
• malformations of cardiovascular system
• a/hypo/dys-genesia of thymus, thyroid and
parathyroids
• anomalies of bones and cartilages
germs (buds) of these organs – in the same
region of embryo
The enigma of HOXA3
• phenotype similar to that of Di George
syndrome (22q11 microdeletion) in humans
• but: in 22q11 region – no HOX gene
• homology HoxA3 – HOXA3 (7p15)
• hypothesis: a gene localized in 22q11
modulates the function of HOXA3
GSCL=goosecoid-like homeobox gene
organization of structures originating from
branchia arcs (bows) and pockets (part of the
skull, thymus, parathyroids, heart, main
arterial truncs)
locus: 22q11.2: the smallest region of deletion
(critical region) of di George syndrome
Clinical results of homeobox gene
mutations
HOX genes:
HOXA13  hand-foot-genital s. (A,D)
HOXD13  polysyndactyly (A,D)
non-HOX genes :
EMX2  schizencephaly (split brain)
MSX2  craniosynostosis
Congenital malformations syndromes
caused by homeobox gene mutations
- exceptionally rare
Causes:
1/high degree of homology between paralogic
(orthologic) HOX genes from different
complexes
 full (or almost full) compensation
2/lethality of mutations of non-HOX homeobox
genes
PAX genes
• Paired HOX genes
• homeobox - 360 nucleotides
• homeodomain – about 128 aminoacids
PAX 2
- optic nerve malformations or hypoplasia
- kidneys dysplasia
PAX
PAX 3
- expression in early neurogenesis
abnormal migration of cells originating
from primordial (primitive) neural tube
(+ abnormal function of N-CAM)
Waardenburg I syndrome (deafness,
abnormal ocular globe, hypertelorism,
pigmentation disorders)
PAX genes
PAX 6
- aniridia (heterozygotes)
- anophthalmia (homozygotes)
localized near WT1 gene (11p13)
microdeletion of this region
 WAGR syndrome (aniridia+Wilms tumor)
HOX genes and integrins
• localization of the genes in the adjacent loci
of the same chromosomes
• integrins genes – also paralogic
• parallel evolution of these two groups of
genes = joint (simultaneous) evolution of
information on organism structure plan (HOX
genes) with evolution of information about
interactions and migrations of cells, which fill
up this structure (integrins genes)
HOX genes and integrins
• localization of genes in the adjacent loci of
the same chromosomes
• integrins genes – also paralogic
• parallel evolution of these two groups of
genes = joint (simultaneous) evolution of
information on organism structure plan (HOX
genes) with evolution of information about
interactions and migrations of cells, which fill
up this structure (integrins genes)
HOX genes and integrins
• localization of genes in the adjacent loci of
the same chromosomes
• integrins genes – also paralogic
• parallel evolution of these two groups of
genes = simultaneous evolution of
information on organism structure plan (HOX
genes) with evolution of information on
interactions and migrations of cells, which fill
up this structure (integrins genes)
Homeobox genes and cancer
• homeobox genes coordinate function of
many genes taking part in pathogenesis of
cancer
• excessive or deregulated expression of
homeobex genes (coding for transcription
factors) – molecular basis of many cancers
• some homeobox genes = cellular
protooncogenes
Homeobox genes and cancer
• homeobox genes coordinate function of
many genes taking part in pathogenesis of
cancer
• excessive or deregulated expression of
homeobex genes (coding for transcription
factors) – molecular basis of many cancers
• some homeobox genes = cellular
protooncogenes
Homeobox genes and cancer
• homeobox genes coordinate function of
many genes taking part in pathogenesis of
cancer
• excessive or deregulated expression of
homeobex genes (coding for transcription
factors) – molecular basis of many cancers
• some homeobox genes = cellular
protooncogenes
Homeobox genes and metastases
• Transplanted tissues preserve pattern of
expression of homeobox genes from
primary localization
• Cancer metastases – analogically (pattern
of homeobox gene expression of primary
tumor and also normal tissue of origin).
Constellation of expression of homeobox
genes is not characteristic for tissue of
metastase localization
Homeobox genes and metastases
• pattern of expression of homeobox
genes = index of histological type of
primary tumor ?
• a role in the diagnostics of unidentified
primary tumors on the basis of
homeobox pattern of metastasis (when
histopathological type – not known)?
Cancer cells
• pattern of homeobox gene expression is
characteristic of tissue of origin
• cancers metastasize according to
information given by these genes
(nonrandom, „programmed” localization
of metastases for a given cancer type)