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HOMEOBOX GENES From Drosophila melanogaster to pathogenesis of congenital malformations in Homo sapiens Olga Haus.

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Presentation on theme: "HOMEOBOX GENES From Drosophila melanogaster to pathogenesis of congenital malformations in Homo sapiens Olga Haus."— Presentation transcript:

1 HOMEOBOX GENES From Drosophila melanogaster to pathogenesis of congenital malformations in Homo sapiens Olga Haus

2 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)

3 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

4 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

5 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)

6 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

7 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

8 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

9 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

10 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

11 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

12 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

13 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

14 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

15 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

16 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

17 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

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19 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

20 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

21 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

22 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

23 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

24 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

25 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

26 PAX genes Paired HOX genes homeobox nucleotides homeodomain – about 128 aminoacids PAX 2 - optic nerve malformations or hypoplasia - kidneys dysplasia

27 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)

28 PAX genes PAX 6 - aniridia (heterozygotes) -anophthalmia (homozygotes) localized near WT1 gene (11p13) microdeletion of this region  WAGR syndrome (aniridia+Wilms tumor)

29 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)

30 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)

31 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)

32 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

33 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

34 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

35 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

36 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)?

37 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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