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 GENESmolecular 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









HOMEOBOXhomeotic 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






HOX genes in humans






HOX genes in humans






LINEAR ORDER OF HOX GENESof 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 neurogenesisabnormal 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)


• localization of genes in the adjacent loci of the same chromosomes


• 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)


• localization of genes in the adjacent loci of the same chromosomes


• 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 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)

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HOMEOBOX GENES